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Kumar N, Kumar B, Ashique S, Yasmin S, Venkatesan K, Islam A, Ghosh S, Sahu A, Bhui U, Ansari MY. A critical review on SGLT2 inhibitors for diabetes mellitus, renal health, and cardiovascular conditions. Diabetes Res Clin Pract 2025; 221:112050. [PMID: 39965722 DOI: 10.1016/j.diabres.2025.112050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally formulated to reduce blood glucose levels in individuals with diabetes. Recent clinical trials indicate that this compound can be repurposed for other critical conditions. A literature search was performed on PubMed, Scopus, Embase, ProQuest, and Google Scholar, utilizing key terms such as SGLT2i, diabetes, and oxidative stress. SGLT2i has significant beneficial effects not only in cardiovascular disease but also in renal dysfunction. SGLT2i therapy can mitigate critical cardiovascular complications like heart attacks, strokes, mortality rates, and hospitalization duration, as well as delay the necessity for dialysis irrespective of diabetic condition. Evidence supports potential advantages of SGLT2 inhibitors for individuals with renal problems and heart failure, regardless of diabetes status. In addition to diabetic mellitus, this analysis explores the latest updates on SGLT2i and the therapeutic advantages it offers in many renal and cardiovascular diseases (CVDs).
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Affiliation(s)
- Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Bimlesh Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Sumel Ashique
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India.
| | - Sabina Yasmin
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Kumar Venkatesan
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
| | - Anas Islam
- Faculty of Pharmacy, Integral University, Lucknow 226026, Uttar Pradesh, India
| | - Suman Ghosh
- Division of Pharmaceutical Chemistry, Guru Nanak Institute of Pharmaceutical Science and Technology, 157/F, Nilgunj Road, Kolkata, West Bengal 700114, India
| | - Anwesha Sahu
- Division of Pharmacology, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Utpal Bhui
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India
| | - Mohammad Yousuf Ansari
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana 133207, India; Ibne Seena College of Pharmacy, Azmi Vidya Nagri Anjhi Shahabad, Hardoi, Uttar Pradesh (U.P.) 241124, India.
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Spellman MJ, Assaf T, Nangia S, Fernandez J, Nicholson KC, Shepard BD. Handling the sugar rush: the role of the renal proximal tubule. Am J Physiol Renal Physiol 2024; 327:F1013-F1025. [PMID: 39447117 PMCID: PMC11687834 DOI: 10.1152/ajprenal.00265.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 10/26/2024] Open
Abstract
Blood glucose homeostasis is critical to ensure the proper functioning of the human body. Through the processes of filtration, reabsorption, secretion, and metabolism, much of this task falls to the kidneys. With a rise in glucose and other added sugars, there is an increased burden on this organ, mainly the proximal tubule, which is responsible for all glucose reabsorption. In this review, we focus on the current physiological and cell biological functions of the renal proximal tubule as it works to reabsorb and metabolize glucose and fructose. We also highlight the physiological adaptations that occur within the proximal tubule as sugar levels rise under pathophysiological conditions including diabetes. This includes the detrimental impacts of an excess glucose load that leads to glucotoxicity. Finally, we explore some of the emerging therapeutics that modulate renal glucose handling and the systemic protection that can be realized by targeting the reabsorptive properties of the kidney.
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Affiliation(s)
- Michael J Spellman
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Tala Assaf
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Shivani Nangia
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Joel Fernandez
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Kyle C Nicholson
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
| | - Blythe D Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia, United States
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Sasako T. Exploring mechanisms of insulin action and strategies to treat diabetes. Endocr J 2024; 71:651-660. [PMID: 38811207 DOI: 10.1507/endocrj.ej24-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/31/2024] Open
Abstract
Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.
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Affiliation(s)
- Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
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Szablewski L. Changes in Cells Associated with Insulin Resistance. Int J Mol Sci 2024; 25:2397. [PMID: 38397072 PMCID: PMC10889819 DOI: 10.3390/ijms25042397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.
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Affiliation(s)
- Leszek Szablewski
- Chair and Department of General Biology and Parasitology, Medical University of Warsaw, Chałubińskiego Str. 5, 02-004 Warsaw, Poland
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Liang LL, He MF, Zhou PP, Pan SK, Liu DW, Liu ZS. GSK3β: A ray of hope for the treatment of diabetic kidney disease. FASEB J 2024; 38:e23458. [PMID: 38315453 DOI: 10.1096/fj.202302160r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/09/2023] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3β (glycogen synthase kinase 3β), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3β participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3β in DKD and its damage mechanism in different intrinsic renal cells. GSK3β is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3β inhibitors on DKD are also discussed.
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Affiliation(s)
- Lu-Lu Liang
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Meng-Fei He
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Pan-Pan Zhou
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Shao-Kang Pan
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Dong-Wei Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
| | - Zhang-Suo Liu
- Traditional Chinese Medicine Integrated Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P.R. China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, P.R. China
- Henan Province Research Center For Kidney Disease, Zhengzhou, P.R. China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, P.R. China
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Li H, Chen W, Lin X, Chen W, Xie T, Chen K, Hou S, Li H. Influence of renal function on the ability of TyG Index to predict all-cause mortality. Lipids Health Dis 2023; 22:193. [PMID: 37951945 PMCID: PMC10638822 DOI: 10.1186/s12944-023-01958-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 10/30/2023] [Indexed: 11/14/2023] Open
Abstract
BACKGROUND The association between triglyceride-glucose (TyG) index and poor prognosis remains controversial. Whether renal function status affects the ability of the TyG index to predict poor prognosis has not yet been elucidated and merits further studies. METHODS This retrospective cohort study included 22,031 participants from communities in the U.S. By juxtaposing the TyG categories with the estimated glomerular filtration rate (eGFR, either < 60 mL/min/1.73m2 or ≥ 60 mL/min/1.73m2), participants were categorized into four distinct groups: (1) TyG_L/eGFR_H; (2) TyG_H/eGFR_H; (3) TyG_L/eGFR_L; and (4) TyG_H/eGFR_L. The endpoint was the all-cause mortality rate. Standard Kaplan-Meier plots were constructed and multifactor Cox regression analyses were carried out and restricted cubic spline regression analysis was utilized to assess the association between death and the TyG index for different renal function statuses. RESULTS No statistical differences were found in the TyG groups in participants with normal renal function after adjustment for all covariates (P = 0.070). However, in the high TyG index group with renal insufficiency, the risk of all-cause mortality rates was reduced by 18%. (HR, 0.82; CI, 0.69-0.98). The TyG index (high vs. low) and renal function (eGFR < 60 vs. eGFR ≥ 60) had statistically significant interactions with death (P < 0.001). When all covariates were adjusted, the risk of mortality for the TyG_L combined with eGFR_L group was 56% higher than that for the TyG_L combined with eGFR_H group (HR, 1.56; CI, 1.33-1.82). In the renal insufficiency population, a nonlinear relationship was observed between mortality and the TyG index, albeit with a differing pattern (P for nonlinearity < 0.001). CONCLUSIONS While it has been known that TyG index was a prognosis marker of CVD, this research highlights that higher TyG index was associated with higher all-cause mortality rates for all participants. Furthermore, renal function status significantly moderates the effect of the TyG index on all-cause mortality in community-dwelling adults.
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Affiliation(s)
- Huilan Li
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Weihua Chen
- Beijing Friendship Hospital, Capital Medical University, Beijing, 100053, China
| | - Xueqin Lin
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Weiqin Chen
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Tingzheng Xie
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350000, China
| | - Kaihong Chen
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China
| | - Shuhong Hou
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China.
| | - Huaqing Li
- Longyan First Affiliated Hospital of Fujian Medical University, Longyan, 364000, China.
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Jin ES, Wen X, Malloy CR. Isotopomer analyses with the tricarboxylic acid cycle intermediates and exchanging metabolites from the rat kidney. NMR IN BIOMEDICINE 2023; 36:e4994. [PMID: 37392148 DOI: 10.1002/nbm.4994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 07/03/2023]
Abstract
Renal metabolism is essential for kidney functions and energy homeostasis in the body. The TCA cycle is the hub of metabolism, but the metabolic activities of the cycle in the kidney have rarely been investigated. This study is to assess metabolic processes at the level of the TCA cycle in the kidney based on isotopomer distributions in multiple metabolites. Isolated rat kidneys were perfused with media containing common substrates including lactate and alanine for an hour. One group of kidneys received [U-13 C3 ]lactate instead of natural abundance lactate while the other group received [U-13 C3 ]alanine instead of natural abundance alanine. Perfused kidneys and effluent were prepared for analysis using NMR spectroscopy. 13 C-labeling patterns in glutamate, fumarate, aspartate and succinate from the kidney extracts showed that pyruvate carboxylase and oxidative metabolism through the TCA cycle were comparably very active, but pyruvate cycling and pyruvate dehydrogenase were relatively less active. Isotopomer analyses with fumarate and malate from effluent, however, indicated that pyruvate carboxylase was much more active than the TCA cycle and other metabolic processes. The reverse equilibrium of oxaloacetate with four-carbon intermediates of the cycle was nearly complete (92%), based on the ratio of [2,3,4-13 C3 ]/[1,2,3-13 C3 ] in aspartate or malate. 13 C enrichment in glucose with 13 C-lactate supply was higher than that with 13 C-alanine. Isotopomer analyses with multiple metabolites (i.e., glutamate, fumarate, aspartate, succinate and malate) allowed us to assess relative metabolic processes in the TCA cycle in the kidney supplied with [U-13 C3 ]lactate. Data from the analytes were generally consistent, indicating highly active pyruvate carboxylase and oxidative metabolism through the TCA cycle. Different 13 C-labeling patterns in analytes from the kidney extracts versus effluent suggested metabolic compartmentalization.
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Affiliation(s)
- Eunsook S Jin
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Xiaodong Wen
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Craig R Malloy
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- VA North Texas Health Care System, Dallas, Texas, USA
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Daza-Arnedo R, Rico-Fontalvo J, Aroca-Martínez G, Rodríguez-Yanez T, Martínez-Ávila MC, Almanza-Hurtado A, Cardona-Blanco M, Henao-Velásquez C, Fernández-Franco J, Unigarro-Palacios M, Osorio-Restrepo C, Uparella-Gulfo I. Insulin and the kidneys: a contemporary view on the molecular basis. FRONTIERS IN NEPHROLOGY 2023; 3:1133352. [PMID: 37675359 PMCID: PMC10479562 DOI: 10.3389/fneph.2023.1133352] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 07/07/2023] [Indexed: 09/08/2023]
Abstract
Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.
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Affiliation(s)
- Rodrigo Daza-Arnedo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | - Jorge Rico-Fontalvo
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | - Gustavo Aroca-Martínez
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
- Faculty of Medicine, Universidad Simón Bolívar, Barranquilla, Colombia
| | | | | | | | - María Cardona-Blanco
- Department of Nephrology, Colombian Association of Nephrology, Cartagena, Colombia
| | | | - Jorge Fernández-Franco
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
| | - Mario Unigarro-Palacios
- Department of Internal Medicine, Endocrinology Fellowship, Fundación Universitaria de Ciencias de la Salud—Hospital San José, Bogotá, Colombia
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Sahoo B, Srivastava M, Katiyar A, Ecelbarger C, Tiwari S. Liver or kidney: Who has the oar in the gluconeogenesis boat and when? World J Diabetes 2023; 14:1049-1056. [PMID: 37547592 PMCID: PMC10401452 DOI: 10.4239/wjd.v14.i7.1049] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 07/12/2023] Open
Abstract
Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source vs the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.
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Affiliation(s)
- Biswajit Sahoo
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Medha Srivastava
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Arpit Katiyar
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, DC 20057, United States
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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10
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Rebelos E, Mari A, Oikonen V, Iida H, Nuutila P, Ferrannini E. Evaluation of renal glucose uptake with [ 18F]FDG-PET: Methodological advancements and metabolic outcomes. Metabolism 2023; 141:155382. [PMID: 36565992 DOI: 10.1016/j.metabol.2022.155382] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/06/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND/PURPOSE Studying renal glucose metabolism non-invasively in humans is an unmet need. Positron emission tomography (PET) is the current gold standard for measuring regional tissue glucose uptake rates, but the most widely used glucose analog ([18F]FDG) is not a good substrate for sodium-glucose cotransporters (SGLTs). As a consequence, [18F]FDG spills over into the urine and [18F]FDG-PET considerably underestimates published rates of whole renal glucose uptake obtained using the arterial-venous difference technique. Our aim was to assess whether [18F]FDG-PET can be used in the study of renal glucose metabolism in humans. METHODS We measured individual [18F]FDG radioactivity in the urine and estimated intraluminal [18F]FDG radioactivity concentration; these values were used to correct renal [18F]FDG-PET data acquired ∼90 min from tracer injection under fasting conditions and during an insulin clamp in 9 lean and 16 obese subjects. RESULTS We found that the corrected glucose uptake is consistently higher in the medulla than cortex and that both cortical and medullary glucose uptake are higher in lean than obese participants under both fasting and insulinized conditions. Moreover, cortical but not medullary glucose uptake is increased from the fasting to the insulinized condition. CONCLUSION The data show for the first time that [18F]FDG-PET can still provide relevant physiological information on regional renal glucose uptake on the condition that [18F]FDG uptake is corrected for tubular radioactivity.
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Affiliation(s)
- Eleni Rebelos
- Turku PET Centre, University of Turku, Turku, Finland; CNR Institute of Clinical Physiology, Pisa, Italy.
| | - Andrea Mari
- CNR Institute of Neuroscience, Padova, Italy
| | - Vesa Oikonen
- Turku PET Centre, University of Turku, Turku, Finland
| | - Hidehiro Iida
- Turku PET Centre, University of Turku, Turku, Finland
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland
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11
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Zhang X, Chao P, Zhang L, Xu L, Cui X, Wang S, Wusiman M, Jiang H, Lu C. Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease. Front Immunol 2023; 14:1030198. [PMID: 37063851 PMCID: PMC10091903 DOI: 10.3389/fimmu.2023.1030198] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 02/16/2023] [Indexed: 03/31/2023] Open
Abstract
BackgroundThere is a growing public concern about diabetic kidney disease (DKD), which poses a severe threat to human health and life. It is important to discover noninvasive and sensitive immune-associated biomarkers that can be used to predict DKD development. ScRNA-seq and transcriptome sequencing were performed here to identify cell types and key genes associated with DKD.MethodsHere, this study conducted the analysis through five microarray datasets of DKD (GSE131882, GSE1009, GSE30528, GSE96804, and GSE104948) from gene expression omnibus (GEO). We performed single-cell RNA sequencing analysis (GSE131882) by using CellMarker and CellPhoneDB on public datasets to identify the specific cell types and cell-cell interaction networks related to DKD. DEGs were identified from four datasets (GSE1009, GSE30528, GSE96804, and GSE104948). The regulatory relationship between DKD-related characters and genes was evaluated by using WGCNA analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) datasets were applied to define the enrichment of each term. Subsequently, immune cell infiltration between DKD and the control group was identified by using the “pheatmap” package, and the connection Matrix between the core genes and immune cell or function was illuminated through the “corrplot” package. Furthermore, RcisTarget and GSEA were conducted on public datasets for the analysis of the regulation relationship of key genes and it revealed the correlation between 3 key genes and top the 20 genetic factors involved in DKD. Finally, the expression of key genes between patients with 35 DKD and 35 healthy controls were examined by ELISA, and the relationship between the development of DKD rate and hub gene plasma levels was assessed in a cohort of 35 DKD patients. In addition, we carried out immunohistochemistry and western blot to verify the expression of three key genes in the kidney tissue samples we obtained.ResultsThere were 8 cell types between DKD and the control group, and the number of connections between macrophages and other cells was higher than that of the other seven cell groups. We identified 356 different expression genes (DEGs) from the RNA-seq, which are enriched in urogenital system development, kidney development, platelet alpha granule, and glycosaminoglycan binding pathways. And WGCNA was conducted to construct 13 gene modules. The highest correlations module is related to the regulation of cell adhesion, positive regulation of locomotion, PI3K-Akt, gamma response, epithelial-mesenchymal transition, and E2F target signaling pathway. Then we overlapped the DEGs, WGCNA, and scRNA-seq, SLIT3, PDE1A and CFH were screened as the closely related genes to DKD. In addition, the findings of immunological infiltration revealed a remarkable positive link between T cells gamma delta, Macrophages M2, resting mast cells, and the three critical genes SLIT3, PDE1A, and CFH. Neutrophils were considerably negatively connected with the three key genes. Comparatively to healthy controls, DKD patients showed high levels of SLIT3, PDE1A, and CFH. Despite this, higher SLIT3, PDE1A, and CFH were associated with an end point rate based on a median follow-up of 2.6 years. And with the gradual deterioration of DKD, the expression of SLIT3, PDE1A, and CFH gradually increased.ConclusionsThe 3 immune-associated genes could be used as diagnostic markers and therapeutic targets of DKD. Additionally, we found new pathogenic mechanisms associated with immune cells in DKD, which might lead to therapeutic targets against these cells.
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Affiliation(s)
- Xueqin Zhang
- Department of Nephropathy, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Peng Chao
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Lei Zhang
- Department of Endocrine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Lin Xu
- Department of Rheumatology Immunology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Xinyue Cui
- Department of Nephropathy, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Shanshan Wang
- Department of Nephropathy, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Miiriban Wusiman
- Department of Nephropathy, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
| | - Hong Jiang
- Department of Nephropathy, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
- Nephrology Clinical Research Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
- *Correspondence: Chen Lu, ; Hong Jiang,
| | - Chen Lu
- Nephrology Clinical Research Center, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumuqi, Xinjiang Uygur Autonomous Region, China
- Department of Nephropathy, The First Affiliated Hospital of Xinjiang Medical University, Urumuqi, Xinjiang Uygur Autonomous Region, China
- *Correspondence: Chen Lu, ; Hong Jiang,
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Alqallaf A, Swan P, Docherty NG. Renal insulin resistance in type 2 diabetes mellitus and progression of chronic kidney disease: potential pathogenic mechanisms. Expert Rev Endocrinol Metab 2022; 17:523-532. [PMID: 36203374 DOI: 10.1080/17446651.2022.2131534] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/28/2022] [Indexed: 01/06/2023]
Abstract
INTRODUCTION A bidirectional association exists between insulin resistance (IR) and chronic kidney disease (CKD) in Type 2 Diabetes Mellitus (T2DM). Baseline measures of IR are predictive of CKD progression, and uremia in progressive CKD is itself, in turn, associated with a worsening of IR. Pre-clinical research reveals that intrinsic IR in glomerular podocytes and the renal tubule may serve as a pathogenic driver of CKD in T2DM. AREAS COVERED The present manuscript takes as its point of departure, the recently identified prognostic utility of severe insulin resistance as a predictor of CKD in T2DM. Findings from a series of studies describing the association of IR with pathological alterations in both established, and less commonly assessed dynamic measures of renal impairment are discussed. Drawing upon the pre-clinical mechanistic evidence base, the cellular and molecular basis of intrinsic renal IR as a promoter of CKD is considered. EXPERT OPINION Measurement of insulin sensitivity may add value to profiling of renal risk in T2DM. Rational selection of therapeutic strategies targeting the enhancement of insulin sensitivity merits special attention regarding the personalized management of CKD in insulin resistance predominant T2DM.
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Affiliation(s)
- Alrataj Alqallaf
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick Swan
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
| | - Neil G Docherty
- Diabetes Complications Research Centre, Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Dublin, Ireland
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Nakamura M, Satoh N, Horita S, Nangaku M. Insulin-induced mTOR signaling and gluconeogenesis in renal proximal tubules: A mini-review of current evidence and therapeutic potential. Front Pharmacol 2022; 13:1015204. [PMID: 36299884 PMCID: PMC9589488 DOI: 10.3389/fphar.2022.1015204] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/27/2022] [Indexed: 12/02/2022] Open
Abstract
Energy is continuously expended in the body, and gluconeogenesis maintains glucose homeostasis during starvation. Gluconeogenesis occurs in the liver and kidneys. The proximal tubule is the primary location for renal gluconeogenesis, accounting for up to 25% and 60% of endogenous glucose production during fasting and after a meal, respectively. The mechanistic target of rapamycin (mTOR), which exists downstream of the insulin pathway, plays an important role in regulating proximal tubular gluconeogenesis. mTOR is an atypical serine/threonine kinase present in two complexes. mTORC1 phosphorylates substrates that enhance anabolic processes such as mRNA translation and lipid synthesis and catabolic processes such as autophagy. mTORC2 regulates cytoskeletal dynamics and controls ion transport and proliferation via phosphorylation of SGK1. Therefore, mTOR signaling defects have been implicated in various pathological conditions, including cancer, cardiovascular disease, and diabetes. However, concrete elucidations of the associated mechanisms are still unclear. This review provides an overview of mTOR and describes the relationship between mTOR and renal.
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Affiliation(s)
- Motonobu Nakamura
- Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
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Yu W, Wang T, Wu F, Zhang Y, Shang J, Zhao Z. Identification and validation of key biomarkers for the early diagnosis of diabetic kidney disease. Front Pharmacol 2022; 13:931282. [PMID: 36071835 PMCID: PMC9441656 DOI: 10.3389/fphar.2022.931282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/22/2022] [Indexed: 12/02/2022] Open
Abstract
Background: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. This study explored the core genes and pathways associated with DKD to identify potential diagnostic and therapeutic targets. Methods: We downloaded microarray datasets GSE96804 and GSE104948 from the Gene Expression Omnibus (GEO) database. The dataset includes a total of 53 DKD samples and 41 normal samples. Differentially expressed genes (DEGs) were identified using the R package “limma”. The Metascape database was subjected to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to identify the pathway and functional annotations of DEGs. A WGCAN network was constructed, the hub genes in the turquoise module were screened, and the core genes were selected using LASSO regression to construct a diagnostic model that was then validated in an independent dataset. The core genes were verified by in vitro and in vivo experiments. Results: A total of 430 DEGs were identified in the GSE96804 dataset, including 285 upregulated and 145 downregulated DEGs. WGCNA screened out 128 modeled candidate gene sets. A total of eight genes characteristic of DKD were identified by LASSO regression to build a prediction model. The results showed accuracies of 99.15% in the training set (GSE96804) and 94.44% and 100%, respectively, in the test (GSE104948-GPL22945 and GSE104948-GPL24120). Three core genes (OAS1, SECTM1, and SNW1) with high connectivity were selected among the modeled genes. In vitro and in vivo experiments confirmed the upregulation of these genes. Conclusion: Bioinformatics analysis combined with experimental validation identified three novel DKD-specific genes. These findings may advance our understanding of the molecular basis of DKD and provide potential therapeutic targets for its clinical management.
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Affiliation(s)
- Wei Yu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Ting Wang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Feng Wu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Yiding Zhang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
| | - Jin Shang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Zhanzheng Zhao, ; Jin Shang,
| | - Zhanzheng Zhao
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Nephrology, Zhengzhou University, Zhengzhou, China
- Laboratory Animal Platform of Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
- Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Zhanzheng Zhao, ; Jin Shang,
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Zhong B, Ma S, Wang DH. Activation of TRPV1 improves natriuresis and salt sensitivity in high-fat diet fed mice. Biochem Pharmacol 2022; 203:115190. [PMID: 35905972 DOI: 10.1016/j.bcp.2022.115190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/02/2022]
Abstract
Western diet (WD) intake increases morbidity of obesity and salt-sensitive hypertension albeit mechanisms are largely unknown. We investigated the role of transient receptor potential vanilloid 1 (TRPV1) in WD intake-induced hypertension. TRPV1-/- and wild-type (WT) mice were fed a normal (CON) or Western diet (WD) for 16-18 weeks. Mean arterial pressure (MAP) after normal sodium glucose (NSG) loading with or without L-NAME (a NO synthase inhibitor) or N-oleoyldopamine (OLDA, a TRPV1agonist) was not different between the two strains on CON.WT or TRPV1-/- mice fed WD had increased MAP after NSG, with a greater magnitude in TRPV1-/- mice. OLDA decreased while L-NAME increased MAP in WT-WD but not in TRPV1-/--WD mice. The urinary nitrates plus nitrites excretion (UNOx), an indicator of renal NO production, was increased in both strains on CON after NSG. TRPV1 ablation with WD intake abolished NSG-induced increment in UNOx. OLDA further increased while L-NAME prevented NSG-induced increment in UNOx in WT-WD mice. Urinary sodium excretion was increased in both strains on CON and in WT-WD mice but not in TRPV1-/--WD mice after NSG. OLDA further increased while L-NAME prevented NSG-induced increases in sodium excretion in WT-WD but not in TRPV1-/--WD mice. Thus, TRPV1 ablation increases salt sensitivity during WD intake possibly via impaired renal NO production and sodium excretion. Activation of TRPV1 enhances renal NO production and sodium excretion, resulting in prevention of increased salt sensitivity during WD intake.
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Affiliation(s)
- Beihua Zhong
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Shuangtao Ma
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Donna H Wang
- Division of Nanomedicine and Molecular Intervention, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA; Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA; Cell & Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA.
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Sharma R, Sahoo B, Srivastava A, Tiwari S. Reduced insulin signaling and high glucagon in early insulin resistance impaired fast-fed regulation of renal gluconeogenesis via insulin receptor substrate. J Cell Biochem 2022; 123:1327-1339. [PMID: 35644013 DOI: 10.1002/jcb.30294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 05/11/2022] [Accepted: 05/18/2022] [Indexed: 11/08/2022]
Abstract
Gluconeogenesis is one of the key processes through which the kidney contributes to glucose homeostasis. Urinary exosomes (uE) have been used to study renal gene regulation noninvasively in humans and rodents. Recently, we demonstrated fast-fed regulation of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme for gluconeogenesis, in human uE. The regulation was impaired in subjects with early insulin resistance. Here, we studied primary human proximal tubule cells (hPT) and human uE to elucidate a potential link between insulin resistance and fast-fed regulation of renal PEPCK. We demonstrate that fasted hPTs had higher PEPCK and insulin receptor substrate-2 (IRS2) mRNA and protein levels, relative to fed cells. The fast-fed regulation was, however, attenuated in insulin receptor knockdown (IRKO) hPTs. The IRKO was confirmed by the blunted insulin-induced response on PEPCK, PGC1α, p-IR, and p-AKT expression in IRKO cells. Exosomes secreted by the wild-type or IRKO hPT showed similar regulation to the respective hPT. Similarly, in human uE, the relative abundance of IRS-2 mRNA (to IRS1) was higher in the fasted state relative to the fed condition. However, the fast-fed difference was absent in subjects with early insulin resistance. These subjects had higher circulating glucagon levels relative to subjects with optimal insulin sensitivity. Furthermore, in hPT cells, glucagon significantly induced PEPCK and IRS2 gene, and gluconeogenesis. IR knockdown in hPT cells further increased the gene expression levels. Together the data suggest that reduced insulin sensitivity and high glucagon in early insulin resistance may impair renal gluconeogenesis via IRS2 regulation.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Biswajit Sahoo
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Aneesh Srivastava
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Liu X, Du H, Sun Y, Shao L. Role of abnormal energy metabolism in the progression of chronic kidney disease and drug intervention. Ren Fail 2022; 44:790-805. [PMID: 35535500 PMCID: PMC9103584 DOI: 10.1080/0886022x.2022.2072743] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) is a severe clinical syndrome with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal kidney function and energy metabolism disorders are increasingly recognized as an important player in CKD. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase. Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides (SS-31) plays a protective role by stabilizing the mitochondrial inner membrane. Moreover, several drugs are being studied and are predicted to have potential renal protective properties. We propose that the regulation of energy metabolism represents a promising strategy to delay the progression of CKD.
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Affiliation(s)
- Xuyan Liu
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Huasheng Du
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Yan Sun
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
| | - Leping Shao
- Department of Nephrology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China
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Renal Cell Cancer and Obesity. Int J Mol Sci 2022; 23:ijms23063404. [PMID: 35328822 PMCID: PMC8951303 DOI: 10.3390/ijms23063404] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Cancers are a frequent cause of morbidity and mortality. There are many risk factors for tumours, including advanced age, personal or family history of cancer, some types of viral infections, exposure to radiation and some chemicals, smoking and alcohol consumption, as well as obesity. Increasing evidence suggest the role of obesity in the initiation and progression of various cancers, including renal cell carcinoma. Since tumours require energy for their uncontrollable growth, it appears plausible that their initiation and development is associated with the dysregulation of cells metabolism. Thus, any state characterised by an intake of excessive energy and nutrients may favour the development of various cancers. There are many factors that promote the development of renal cell carcinoma, including hypoxia, inflammation, insulin resistance, excessive adipose tissue and adipokines and others. There are also many obesity-related alterations in genes expression, including DNA methylation, single nucleotide polymorphisms, histone modification and miRNAs that can promote renal carcinogenesis. This review focuses on the impact of obesity on the risk of renal cancers development, their aggressiveness and patients’ survival.
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Jeddi S, Gheibi S, Kashfi K, Ghasemi A. Sodium hydrosulfide has no additive effects on nitrite-inhibited renal gluconeogenesis in type 2 diabetic rats. Life Sci 2021; 283:119870. [PMID: 34352258 DOI: 10.1016/j.lfs.2021.119870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Lund University, Malmö, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular, Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Rahman MS, Hossain KS, Das S, Kundu S, Adegoke EO, Rahman MA, Hannan MA, Uddin MJ, Pang MG. Role of Insulin in Health and Disease: An Update. Int J Mol Sci 2021; 22:6403. [PMID: 34203830 PMCID: PMC8232639 DOI: 10.3390/ijms22126403] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023] Open
Abstract
Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.
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Affiliation(s)
- Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Khandkar Shaharina Hossain
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Sharnali Das
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Sushmita Kundu
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
| | - Elikanah Olusayo Adegoke
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
| | - Md. Ataur Rahman
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Md. Abdul Hannan
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
| | - Md Jamal Uddin
- ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh; (K.S.H.); (S.D.); (S.K.); (M.A.R.); (M.A.H.); (M.J.U.)
- Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Woman’s University, Seoul 03760, Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong 17546, Korea; (M.S.R.); (E.O.A.)
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Akhtar S, Culver SA, Siragy HM. Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway. Sci Rep 2021; 11:11367. [PMID: 34059756 PMCID: PMC8167177 DOI: 10.1038/s41598-021-90952-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 05/18/2021] [Indexed: 12/19/2022] Open
Abstract
Recent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.
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Affiliation(s)
- Safia Akhtar
- Department of Medicine, University of Virginia Health System, P.O. Box 801409, Charlottesville, VA, 22903, USA
| | - Silas A Culver
- Department of Medicine, University of Virginia Health System, P.O. Box 801409, Charlottesville, VA, 22903, USA
| | - Helmy M Siragy
- Department of Medicine, University of Virginia Health System, P.O. Box 801409, Charlottesville, VA, 22903, USA.
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Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021; 12:556-568. [PMID: 33995844 PMCID: PMC8107972 DOI: 10.4239/wjd.v12.i5.556] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/27/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Renal gluconeogenesis is one of the major pathways for endogenous glucose production. Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes. We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes. A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up. Insulin-resistant models exhibit reduced insulin receptor (IR) expression and/or post-receptor signaling in their kidney tissue. Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys, which may increase renal gluconeogenesis in the state of insulin resistance. It is now established that the kidney contributes up to 20% of all glucose production via gluconeogenesis in the post-absorptive phase. However, the rate of renal glucose release excessively increases in diabetes. The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels. Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis. Overall, the available literature suggests that impairment in renal gluconeogenesis in an insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Jeddi S, Gheibi S, Carlström M, Kashfi K, Ghasemi A. Long-term co-administration of sodium nitrite and sodium hydrosulfide inhibits hepatic gluconeogenesis in male type 2 diabetic rats: Role of PI3K-Akt-eNOS pathway. Life Sci 2020; 265:118770. [PMID: 33212150 DOI: 10.1016/j.lfs.2020.118770] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE A deficiency in hydrogen sulfide (H2S) and nitric oxide (NO) contributes to the development of type 2 diabetes (T2D). An inhibitory effect on liver gluconeogenesis has been reported in rats with T2D with co-administration of sodium nitrite and sodium hydrosulfide (NaSH); the underlying mechanisms have however not yet been elucidated. The aim of this study is to determine the long-term effects of co-administering sodium nitrite and NaSH on expression of genes involved in liver gluconeogenesis in rats with T2D. METHODS T2D was induced using a high fat diet combined with low-dose of streptozotocin (30 mg/kg). Rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite (50 mg/L) and NaSH (0.28 mg/kg) were administered for 9 weeks. Intraperitoneal pyruvate tolerance test (PTT) was performed at the end of the ninth week and mRNA expressions of PI3K, Akt, eNOS, PEPCK, G6Pase, and FBPase were measured in the liver. RESULTS Co-administration of nitrite and NaSH decreased elevated serum glucose concentrations during PTT. Compared to T2D + nitrite, co-administration of nitrite and NaSH resulted in significant increases in mRNA expression of PI3K, Akt, and eNOS and significant decreases in mRNA expression of G6Pase and FBPase but had no effect on PEPCK expression. CONCLUSION Long-term NaSH administration at low-dose, potentiated the inhibitory effects of nitrite on mRNA expression of key liver gluconeogenic enzymes in rats with T2D. This inhibitory effect of nitrite and NaSH co-administration on gluconeogenesis were associated with increased gene expression of PI3K, Akt, and eNOS in the liver.
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Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Rani L, Saini S, Shukla N, Chowdhuri DK, Gautam NK. High sucrose diet induces morphological, structural and functional impairments in the renal tubules of Drosophila melanogaster: A model for studying type-2 diabetes mediated renal tubular dysfunction. INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY 2020; 125:103441. [PMID: 32735915 DOI: 10.1016/j.ibmb.2020.103441] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 07/13/2020] [Accepted: 07/20/2020] [Indexed: 06/11/2023]
Abstract
Continuous feeding of high dietary sugar is strongly associated with type 2 diabetes (T2D) and its secondary complications. Diabetic nephropathy (DN) is a major secondary complication that leads to glomerular and renal tubular dysfunction. The present study is aimed to investigate the effects of chronic exposure of high sugar diet (HSD) on renal tubules. Malpighian tubules (MTs), a renal organ of Drosophila, were used as a model in the study. Feeding of HSD develops T2D condition in Drosophila. The MTs showed structural abnormalities in 20 days of HSD fed flies. Impaired insulin signaling, oxidative stress, enhanced levels of AGE-RAGE and induction of apoptosis were observed in the MTs of these flies. Further, altered expression of transporters, enhanced uric acid level and reduced fluid secretion rate confirmed the impaired function of MTs in these flies. RNA-seq and RT-PCR analyses in the MTs of HSD fed-and control-flies revealed the altered expression of candidate genes that regulate several important pathways including extracellular matrix (ECM), advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE), transforming growth factor β (TGF-β), galactose, starch and sucrose metabolism that are well known mediators of renal tubular dysfunction in DN patients. Disruption of insulin signaling in the MTs also causes renal tubular dysfunction similar to HSD fed flies. Overall, the study suggests that phenotypes observed in the MTs of HSD fed flies recapitulate several hallmarks of renal tubular dysfunction in DN patients. Therefore, we conclude that MTs of HSD fed flies may be used for deciphering the underlying mechanisms of T2D mediated renal tubular dysfunction.
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Affiliation(s)
- Lavi Rani
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India
| | - Sanjay Saini
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, 226007, India
| | - Neha Shukla
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India
| | - Debapratim Kar Chowdhuri
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India
| | - Naveen Kumar Gautam
- Embryotoxicology Laboratory, Environmental Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31 Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR Campus, Lucknow, India; Department of Urology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226014, Uttar Pradesh, India.
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Rysz J, Franczyk B, Ławiński J, Olszewski R, Gluba-Brzózka A. The Role of Metabolic Factors in Renal Cancers. Int J Mol Sci 2020; 21:E7246. [PMID: 33008076 PMCID: PMC7582927 DOI: 10.3390/ijms21197246] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/25/2020] [Accepted: 09/25/2020] [Indexed: 12/24/2022] Open
Abstract
An increasing number of evidence indicates that metabolic factors may play an important role in the development and progression of certain types of cancers, including renal cell carcinoma (RCC). This tumour is the most common kidney cancer which accounts for approximately 3-5% of malignant tumours in adults. Numerous studies indicated that concomitant diseases, including diabetes mellitus (DM) and hypertension, as well as obesity, insulin resistance, and lipid disorders, may also influence the prognosis and cancer-specific overall survival. However, the results of studies concerning the impact of metabolic factors on RCC are controversial. It appears that obesity increases the risk of RCC development; however, it may be a favourable factor in terms of prognosis. Obesity is closely related to insulin resistance and the development of diabetes mellitus type 2 (DM2T) since the adipocytes in visceral tissue secrete substances responsible for insulin resistance, e.g., free fatty acids. Interactions between insulin and insulin-like growth factor (IGF) system appear to be of key importance in the development and progression of RCC; however, the exact role of insulin and IGFs in RCC pathophysiology remains elusive. Studies indicated that diabetes increased the risk of RCC, but it might not alter cancer-related survival. The risk associated with a lipid profile is most mysterious, as numerous studies provided conflicting results. Even though large studies unravelling pathomechanisms involved in cancer growth are required to finally establish the impact of metabolic factors on the development, progression, and prognosis of renal cancers, it seems that the monitoring of health conditions, such as diabetes, low body mass index (BMI), and lipid disorders is of high importance in clear-cell RCC.
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Affiliation(s)
- Jacek Rysz
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Beata Franczyk
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
| | - Janusz Ławiński
- Department of Urology, Institute of Medical Sciences, Medical College of Rzeszow University, 35-055 Rzeszow, Poland;
| | - Robert Olszewski
- Department of Gerontology, Public Health and Education, National Institute of Geriatrics Rheumatology and Rehabilitation, 02-106 Warsaw, Poland;
- Department of Ultrasound, Institute of Fundamental Technological Research, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Anna Gluba-Brzózka
- Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, 90-549 Lodz, Poland; (J.R.); (B.F.)
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Martins FL, Bailey MA, Girardi ACC. Endogenous Activation of Glucagon-Like Peptide-1 Receptor Contributes to Blood Pressure Control: Role of Proximal Tubule Na +/H + Exchanger Isoform 3, Renal Angiotensin II, and Insulin Sensitivity. Hypertension 2020; 76:839-848. [PMID: 32755467 DOI: 10.1161/hypertensionaha.120.14868] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The pharmacological administration of GLP-1R (glucagon-like peptide-1 receptor) agonists reduces blood pressure (BP) in type 2 diabetes mellitus and nondiabetic patients. This study tested the hypothesis that endogenous GLP-1R signaling influences the regulation of BP. To this end, SHRs (spontaneously hypertensive rats) and Wistar rats were treated with the GLP-1R antagonist Ex9 (exendin-9) or vehicle for 4 weeks. Rats receiving the GLP-1R agonist Ex4 (exenatide) were used as an additional control. We found that blockade of baseline GLP-1R signaling by Ex9 increased systolic BP in both SHR and Wistar rats, compared with vehicle-treated animals, while Ex4 only reduced systolic BP in SHR. Higher systolic BP induced by Ex9 was accompanied by reduced lithium clearance and lower levels of NHE3 (Na+/H+ exchanger isoform 3) phosphorylation at the serine 552, indicative of increased proximal tubule sodium reabsorption. Additionally, urinary AGT (angiotensinogen) and renal cortical concentration of Ang II (angiotensin II) were enhanced by Ex9. Conversely, Ex4 decreased both urinary AGT and cortical Ang II but exclusively in SHRs. Moreover, both SHR and Wistar rats treated with Ex9 displayed hyperinsulinemia as compared with vehicle-treated rats, whereas Ex4 reduced fasting insulin concentration in SHR. Collectively, these results suggest that endogenous GLP-1R signaling exerts a physiologically relevant effect on BP control, which may be attributable, in part, to its tonic actions on the proximal tubule NHE3-mediated sodium reabsorption, intrarenal renin-angiotensin system, and insulin sensitivity. The possible role of impaired GLP-1R signaling in the pathogenesis of hypertension warrants further investigation.
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Affiliation(s)
- Flavia L Martins
- From the Heart Institute (InCor), Medical School, University of São Paulo, Brazil (F.L.M., A.C.C.G.)
| | - Matthew A Bailey
- Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom (M.A.B.)
| | - Adriana C C Girardi
- From the Heart Institute (InCor), Medical School, University of São Paulo, Brazil (F.L.M., A.C.C.G.)
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27
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Sass MR, Wewer Albrechtsen NJ, Pedersen J, Hare KJ, Borbye-Lorenzen N, Kiss K, Vilsbøll T, Knop FK, Poulsen SS, Jørgensen NR, Holst JJ, Ørskov C, Hartmann B. Secretion of parathyroid hormone may be coupled to insulin secretion in humans. Endocr Connect 2020; 9:747-754. [PMID: 32698134 PMCID: PMC7424341 DOI: 10.1530/ec-20-0092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion. METHODS Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR). RESULTS The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min × ng/L and -2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR. CONCLUSION Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.
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Affiliation(s)
- Marie Reeberg Sass
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nicolai Jacob Wewer Albrechtsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Jens Pedersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Endocrinology and Nephrology, Nordsjællands University Hospital, Hillerød, Denmark
| | - Kristine Juul Hare
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Nis Borbye-Lorenzen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark
| | - Katalin Kiss
- Department of Pathology, Rigshospitalet, Copenhagen, Denmark
| | - Tina Vilsbøll
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip Krag Knop
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Steen Seier Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Niklas Rye Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cathrine Ørskov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Correspondence should be addressed to B Hartmann:
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Ferrannini E, Pereira-Moreira R, Seghieri M, Rebelos E, Souza AL, Chueire VB, Arvia C, Muscelli E. Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport. BMJ Open Diabetes Res Care 2020; 8:8/1/e001178. [PMID: 32423964 PMCID: PMC7245398 DOI: 10.1136/bmjdrc-2020-001178] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/27/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known. METHODS We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination. RESULTS During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion. CONCLUSIONS Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.
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Affiliation(s)
| | - Ricardo Pereira-Moreira
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Marta Seghieri
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Eleni Rebelos
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Aglécio L Souza
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Valeria B Chueire
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | | | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil
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Sharma R, Kumari M, Prakash P, Gupta S, Tiwari S. Phosphoenolpyruvate carboxykinase in urine exosomes reflect impairment in renal gluconeogenesis in early insulin resistance and diabetes. Am J Physiol Renal Physiol 2020; 318:F720-F731. [PMID: 32036699 DOI: 10.1152/ajprenal.00507.2019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Impaired insulin-induced suppression of renal gluconeogenesis could be a risk for hyperglycemia. Diabetes is associated with elevated renal gluconeogenesis; however, its regulation in early insulin resistance is unclear in humans. A noninvasive marker of renal gluconeogenesis would be helpful. Here, we show that human urine exosomes (uE) contain three gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Their protein levels were positively associated with whole body insulin sensitivity. PEPCK protein in uE exhibited a meal-induced suppression. However, subjects with lower insulin sensitivity had blunted meal-induced suppression. Also, uE from subjects with prediabetes and diabetic rats had higher PEPCK relative to nondiabetic controls. Moreover, uE-PEPCK was higher in drug-naïve subjects with diabetes relative to drug-treated subjects with diabetes. To determine whether increased renal gluconeogenesis is associated with hyperglycemia or PEPCK expression in uE, acidosis was induced in rats by 0.28 M NH4Cl with 0.5% sucrose in drinking water. Control rats were maintained on 0.5% sucrose. At the seventh day posttreatment, gluconeogenic enzyme activity in the kidneys, but not in the liver, was higher in acidotic rats. These rats had elevated PEPCK in their uE and a significant rise in blood glucose relative to controls. The induction of gluconeogenesis in human proximal tubule cells increased PEPCK expression in both human proximal tubules and human proximal tubule-secreted exosomes in the media. Overall, gluconeogenic enzymes are detectable in human uE. Elevated PEPCK and its blunted meal-induced suppression in human urine exosomes are associated with diabetes and early insulin resistance.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Prem Prakash
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sushil Gupta
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Pereira-Moreira R, Muscelli E. Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review. J Diabetes Res 2020; 2020:8492467. [PMID: 32377524 PMCID: PMC7180501 DOI: 10.1155/2020/8492467] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 12/18/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023] Open
Abstract
Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.
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Affiliation(s)
- Ricardo Pereira-Moreira
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
| | - Elza Muscelli
- Department of Internal Medicine, School of Medical Sciences, University of Campinas, Zip Code: 13083-887, Brazil
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31
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Westermeier F, Holyoak T, Asenjo JL, Gatica R, Nualart F, Burbulis I, Bertinat R. Gluconeogenic Enzymes in β-Cells: Pharmacological Targets for Improving Insulin Secretion. Trends Endocrinol Metab 2019; 30:520-531. [PMID: 31213347 DOI: 10.1016/j.tem.2019.05.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic β-cells express the gluconeogenic enzymes glucose 6-phosphatase (G6Pase), fructose 1,6-bisphosphatase (FBP), and phosphoenolpyruvate (PEP) carboxykinase (PCK), which modulate glucose-stimulated insulin secretion (GSIS) through their ability to reverse otherwise irreversible glycolytic steps. Here, we review current knowledge about the expression and regulation of these enzymes in the context of manipulating them to improve insulin secretion in diabetics. Because the regulation of gluconeogenic enzymes in β-cells is so poorly understood, we propose novel research avenues to study these enzymes as modulators of insulin secretion and β-cell dysfunction, with especial attention to FBP, which constitutes an attractive target with an inhibitor under clinical evaluation at present.
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Affiliation(s)
- Francisco Westermeier
- FH JOANNEUM Gesellschaft mbH University of Applied Sciences, Institute of Biomedical Science, Eggenberger Allee 13, 8020 Graz, Austria
| | - Todd Holyoak
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
| | - Joel L Asenjo
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Independencia 631, 5110566 Valdivia, Chile
| | - Rodrigo Gatica
- Escuela de Veterinaria, Facultad de Ciencias, Universidad Mayor, La Pirámide 5750, 8580745 Santiago, Chile
| | - Francisco Nualart
- Centro de Microscopía Avanzada, CMA BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160 C, 4030000 Concepción, Chile
| | - Ian Burbulis
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Jordan Hall Room 6022, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA; Escuela de Medicina, Universidad San Sebastián, Sede Patagonia, Lago Panguipulli 1390, 5501842 Puerto Montt, Chile
| | - Romina Bertinat
- Centro de Microscopía Avanzada, CMA BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Casilla 160 C, 4030000 Concepción, Chile.
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32
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Westermeier F, Holyoak T, Gatica R, Martínez F, Negrón M, Yáñez AJ, Nahmias D, Nualart F, Burbulis I, Bertinat R. Cytosolic phosphoenolpyruvate carboxykinase is expressed in α-cells from human and murine pancreas. J Cell Physiol 2019; 235:166-175. [PMID: 31180589 DOI: 10.1002/jcp.28955] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/24/2019] [Indexed: 12/16/2022]
Abstract
The pancreatic islets of Langerhans, mainly formed by glucagon-producing α-cells and insulin-producing β-cells, are critical for glucose homeostasis. Insulin and glucagon oppositely modulate blood glucose levels in health, but a combined decline in insulin secretion together with increased glucagon secretion contribute to hyperglycemia in diabetes. Despite this bi-hormonal dysregulation, most studies have focused on insulin secretion and much less is known about glucagon secretion. Therefore, a deeper understanding of α-cell metabolism and glucagon secretion is of great interest. Here, we show that phosphoenolpyruvate carboxykinase (PCK1), an essential cataplerotic enzyme involved in metabolism and long considered to be absent from the pancreatic islet, is expressed in pancreatic α-cells of both murine and human. Furthermore, PCK1 transcription is induced by fasting and diabetes in rat pancreas, which indicates that the PCK1 activity is required for α-cell adaptation to different metabolic states. To our knowledge, this is the first evidence implicating PCK1 expression in α-cell metabolism.
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Affiliation(s)
- Francisco Westermeier
- FH JOANNEUM Gesellschaft mbH University of Applied Sciences, Institute of Biomedical Science, Department of Health Studies, Graz, Austria
| | - Todd Holyoak
- Department of Biology, University of Waterloo, Waterloo, Ontario, Canada
| | - Rodrigo Gatica
- Escuela de Veterinaria, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Fernando Martínez
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Marianne Negrón
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Alejandro J Yáñez
- Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Daniel Nahmias
- Anatomía patológica, Hospital Puerto Montt, Puerto Montt, Chile
| | - Francisco Nualart
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
| | - Ian Burbulis
- Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, Virginia.,Escuela de Medicina, Universidad San Sebastián, Sede de la Patagonia, Puerto Montt, Chile
| | - Romina Bertinat
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile
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33
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Álvarez-Cilleros D, López-Oliva E, Goya L, Martín MÁ, Ramos S. Cocoa intake attenuates renal injury in Zucker Diabetic fatty rats by improving glucose homeostasis. Food Chem Toxicol 2019; 127:101-109. [DOI: 10.1016/j.fct.2019.03.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 03/01/2019] [Accepted: 03/02/2019] [Indexed: 12/26/2022]
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Solarek W, Koper M, Lewicki S, Szczylik C, Czarnecka AM. Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators. J Cell Commun Signal 2019; 13:381-394. [PMID: 30929166 PMCID: PMC6732138 DOI: 10.1007/s12079-019-00512-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/25/2019] [Indexed: 12/24/2022] Open
Abstract
The risk of renal cell carcinoma development is correlated with obesity and type II diabetes. Since insulin and insulin-like growth factors play a key role during development of both metabolic diseases, these molecules may be important in RCC pathophysiology We investigated the effect of insulin and IGFs on RCC cells using in vitro model with 786-O, 769-P, Caki-1, Caki-2, ACHN cancer cell lines. Cancer cells were compared with normal kidney cells - PCS-400-010 and HEK293. The growth, viability of cells as well as migration rate were assessed upon hormonal stimulation. The insulin receptor and Insulin-like growth factor 1 receptor presence were evaluated and the expression of 84 genes related to insulin signaling pathway. In all RCC cell lines IGF-1R expression was confirmed in contrast to IR, which was expressed only in control HEK293 cell line. Insulin and IGFs stimulated RCC cells growth and migration rate. Insulin, IGF-1 and IGF-2 triggered both IR and IGF-1R phosphorylation. Analyzed RCC did not secret insulin, IGF-1 or IGF-2 and were not activated in autocrine-paracrine signaling loop. Insulin and IGFs stimulations triggered down-regulation of PI3K-Akt-mTOR and Ras-MAPK pathway gens, as well as DOK2-3, INS, FRS3, IRS1-2, IGF1R - genes encoding insulin receptor-associated proteins. In conclusion, we showed that IGFs and insulin may play a stimulatory role for renal cancer cells, thus they can possibly affect renal cancer tumorigenesis and progression on cellular level.
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Affiliation(s)
- Wojciech Solarek
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, Warsaw, 04-141, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Michal Koper
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Slawomir Lewicki
- Department of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology, Warsaw, Poland
| | - Cezary Szczylik
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, Warsaw, 04-141, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.,Department of Oncology, European Health Centre, Otwock, Poland.,Medical Center for Postgraduate Education, Warsaw, Poland
| | - Anna M Czarnecka
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, Warsaw, 04-141, Poland.
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35
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Liu Q, Zhang L, Zhang W, Hao Q, Qiu W, Wen Y, Wang H, Li X. Inhibition of NF-κB Reduces Renal Inflammation and Expression of PEPCK in Type 2 Diabetic Mice. Inflammation 2019; 41:2018-2029. [PMID: 30066289 DOI: 10.1007/s10753-018-0845-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Renal gluconeogenesis is markedly promoted in patients with type 2 diabetes mellitus (T2DM); however, the underlying mechanism remains largely unknown. Renal gluconeogenesis is found to be negatively regulated by insulin. T2DM is characterized by chronic and subacute inflammation; however, inflammation has been well recognized to induce insulin resistance. Therefore, this study aimed to investigate whether the enhanced renal gluconeogenesis in T2DM was partially due to the renal inflammation-mediated insulin resistance. If so, whether inflammation inhibitor could partially reverse such change. Diabetic db/db mice and db/m mice were used in our study. Typically, diabetic db/db mice were intraperitoneally treated with 1 mg/kg NF-κB inhibitor parthenolide (PTN) or saline as control every other day. Twelve weeks after treatment, animal samples were collected for measurements. Our results suggested that the expression levels of the inflammatory factors and the gluconeogenic rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) were up-regulated in renal cortex of both db/db mice and T2DM patients. Moreover, reduced insulin signaling, as well as up-regulated expression of downstream genes FOXO1 and PGC-1ɑ, could be detected in renal cortex of db/db mice compared with that of db/m mice. Consistent with our hypothesis, PTN treatment could alleviate renal inflammation and insulin resistance in db/db mice. Moreover, it could also down-regulate the renal expression of PEPCK, indicating that inflammation could be one of the triggers of insulin resistance and the enhanced renal gluconeogenesis in db/db mice. This study can shed light on the role of inflammation in the enhanced renal gluconeogenesis in T2DM, which may yield a novel target for hyperglycemia.
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Affiliation(s)
- Qianling Liu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Liangyan Zhang
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Wei Zhang
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Qiufa Hao
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Wei Qiu
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yubing Wen
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Haiyun Wang
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xuemei Li
- Department of Nephrology, Peking Union Medical College Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing, 100730, China.
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36
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Singh S, Sharma R, Kumari M, Tiwari S. Insulin receptors in the kidneys in health and disease. World J Nephrol 2019; 8:11-22. [PMID: 30705868 PMCID: PMC6354081 DOI: 10.5527/wjn.v8.i1.11] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/15/2018] [Accepted: 12/10/2018] [Indexed: 02/06/2023] Open
Abstract
Insulin is an important hormone that affects various metabolic processes, including kidney function. Impairment in insulin’s action leads to insulin resistance in the target tissue. Besides defects in post-receptor insulin signaling, impairment at the receptor level could significantly affect insulin sensitivity of the target tissue. The kidney is a known target of insulin; however, whether the kidney develops “insulin resistance” is debatable. Regulation of the insulin receptor (IR) expression and its function is very well studied in major metabolic tissues like liver, skeletal muscles, and adipose tissue. The physiological relevance of IRs in the kidney has recently begun to be clarified. The credit goes to studies that showed a wide distribution of IR throughout the nephron segments and their reduced expression in the insulin resistance state. Moreover, altered renal and systemic metabolism observed in mice with targeted deletion of the IR from various epithelial cells of the kidney has strengthened this proposition. In this review, we recapitulate the crucial findings from literature that have expanded our knowledge regarding the significance of the renal IR in normal- and insulin-resistance states.
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Affiliation(s)
- Sarojini Singh
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Manju Kumari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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37
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Swe MT, Pongchaidecha A, Chatsudthipong V, Chattipakorn N, Lungkaphin A. Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions. J Cell Physiol 2018; 234:8134-8151. [PMID: 30370538 DOI: 10.1002/jcp.27598] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 09/19/2018] [Indexed: 12/12/2022]
Abstract
The kidneys are as involved as the liver in gluconeogenesis which can significantly contribute to hyperglycemia in the diabetic condition. Substantial evidence has demonstrated the overexpression of rate-limiting gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose 6 phosphatase, and the accelerated glucose release both in the isolated proximal tubular cells and in the kidneys of diabetic animal models and diabetic patients. The aim of this review is to provide an insight into the mechanisms that accelerate renal gluconeogenesis in the diabetic conditions and the therapeutic approaches that could affect this process in the kidney. Increase in gluconeogenic substrates, reduced insulin concentration or insulin resistance, downregulation of insulin receptors and insulin signaling, oxidative stress, and inappropriate activation of the renin-angiotensin system are likely to participate in enhancing renal gluconeogenesis in the diabetic milieu. Several studies have suggested that controlling glucose metabolism at the renal level favors effective overall glycemic control in both type 1 and type 2 diabetes. Therefore, renal gluconeogenesis may be a promising target for effective glycemic control as a therapeutic strategy in diabetes.
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Affiliation(s)
- Myat Theingi Swe
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Department of Physiology, University of Medicine 2, Yangon, Myanmar
| | - Anchalee Pongchaidecha
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Varanuj Chatsudthipong
- Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Nipon Chattipakorn
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.,Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
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38
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Álvarez-Cilleros D, Martín MÁ, Ramos S. Protective effects of (-)-epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid against glucotoxicity-induced insulin signalling blockade and altered glucose uptake and production in renal tubular NRK-52E cells. Food Chem Toxicol 2018; 120:119-128. [PMID: 29981789 DOI: 10.1016/j.fct.2018.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 06/26/2018] [Accepted: 07/02/2018] [Indexed: 01/24/2023]
Abstract
Glucotoxicity (high levels of glucose) is a major cause in the pathogenesis of diabetes. Evidences indicate that (-)-epicatechin (EC) and colonic metabolites derived from flavonoid intake could possess antidiabetic effects, but the mechanisms for their preventive activities related to glucose homeostasis and insulin signalling in the kidney remain largely unknown. This work is aimed to investigate the effect of EC and main colonic phenolic acids derived from flavonoid intake, i.e. 2,3-dihydroxybenzoic-acid, 3,4-dihydroxyphenylacetic-acid (DHPAA) and 3-hydroxyphenylpropionic-acid, on insulin signalling, and glucose production and uptake in renal tubular proximal NRK-52E cells treated with high glucose. Pre-treatment with EC or DHPAA prevented the decreased tyrosine-phosphorylated and total levels of IR caused by high glucose. EC and DHPAA pre-treatment also avoided the inactivation of the PI3K/AKT pathway and AMPK, and the elevation of PEPCK levels induced by high glucose. Additionally, EC and DHPAA pre-treatment alleviated the altered glucose uptake and production caused by high glucose, although this protective effect was abrogated when AKT and AMPK were inhibited. These results suggest EC and DHPAA prevent or delay a potential dysfunction of NRK-52E cells treated with high glucose through the attenuation of the insulin signalling blockade and the modulation of glucose homeostasis via AKT and AMPK.
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Affiliation(s)
- David Álvarez-Cilleros
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain
| | - María Ángeles Martín
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Sonia Ramos
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, 28040, Madrid, Spain.
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Álvarez-Cilleros D, Martín MÁ, Ramos S. (-)-Epicatechin and the Colonic 2,3-Dihydroxybenzoic Acid Metabolite Regulate Glucose Uptake, Glucose Production, and Improve Insulin Signaling in Renal NRK-52E Cells. Mol Nutr Food Res 2018; 62. [PMID: 29205863 DOI: 10.1002/mnfr.201700470] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Revised: 11/03/2017] [Indexed: 12/16/2022]
Abstract
SCOPE (-)-Epicatechin (EC) and main colonic phenolic acids derived from flavonoid intake, such as 2,3-dihydroxybenzoic acid (DHBA), 3,4-dihydroxyphenylacetic acid (DHPAA), 3-hydroxyphenylpropionic acid (HPPA), and vanillic acid (VA), have been suggested to exert beneficial effects in diabetes, although the mechanism for their actions remains unknown. In this study, the modulation of glucose homeostasis and insulin signaling by the mentioned compounds on renal proximal tubular NRK-52E cells is investigated. METHODS AND RESULTS Levels of the glucose transporters SGLT-2 and GLUT-2, as well as glucose uptake, glucose production, and key proteins of the insulin pathways, namely insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and PI3K/AKT pathway are analyzed. EC (5-20 μm) and DHBA (20 μm) reduced both renal glucose uptake and production. Interestingly, EC and DHBA did not modify the levels of SGLT-2 and GLUT-2, and modulated the expression of phosphoenolpyruvate carboxykinase via AKT leading to a diminished glucose production. EC and DHBA also enhanced the tyrosine phosphorylation and total IR and IRS-1 levels, and activated the PI3K/AKT pathway in NRK-52E cells. CONCLUSION EC and DHBA regulate the renal glucose homeostasis by modulating both glucose uptake and production, and strengthen the insulin signaling by activating key proteins of that pathway in NRK-52E cells.
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Affiliation(s)
- David Álvarez-Cilleros
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, Madrid, Spain
| | - María Ángeles Martín
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, Madrid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Spain
| | - Sonia Ramos
- Department of Metabolism and Nutrition, Institute of Food Science and Technology and Nutrition (ICTAN), Consejo Superior de Investigaciones Científicas (CSIC), José Antonio Novais 10, Ciudad Universitaria, Madrid, Spain
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40
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Bertinat R, Westermeier F, Silva P, Gatica R, Oliveira JM, Nualart F, Gomis R, Yáñez AJ. The Antidiabetic Agent Sodium Tungstate Induces Abnormal Glycogen Accumulation in Renal Proximal Tubules from Diabetic IRS2-Knockout Mice. J Diabetes Res 2018; 2018:5697970. [PMID: 30003110 PMCID: PMC5996472 DOI: 10.1155/2018/5697970] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/19/2017] [Accepted: 01/28/2018] [Indexed: 11/22/2022] Open
Abstract
The kidney is an insulin-sensitive organ involved in glucose homeostasis. One major effect of insulin is to induce glycogen storage in the liver and muscle. However, no significant glycogen stores are detected in normal kidneys, but diabetic subjects present a characteristic renal histopathological feature resulting from extensive glycogen deposition mostly in nonproximal tubules. The mechanism of renal glycogen accumulation is yet poorly understood. Here, we studied in situ glycogen accumulation in the kidney from diabetic IRS2-knockout mice and the effect of the insulin-mimetic agent sodium tungstate (NaW). IRS2-knockout mice displayed hyperglycemia and hyperinsulinemia. NaW only normalized glycemia. There was no evident morphological difference between kidneys from untreated wild-type (WT), NaW-treated WT, and untreated IRS2-knockout mice. However, NaW-treated IRS2-knockout mice showed tubular alterations resembling clear cells in the cortex, but not in the outer medulla, that were correlated with glycogen accumulation. Immunohistochemical detection of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, mostly expressed by renal proximal tubules, showed that altered tubules were of proximal origin. Our preliminary study suggests that IRS2 differentially regulates glycogen accumulation in renal tubules and that NaW treatment in the context of IRS2 ablation induces abnormal glycogen accumulation in cortical proximal tubules.
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Affiliation(s)
- Romina Bertinat
- Centro de Microscopía Avanzada (CMA BIO-BIO), Universidad de Concepción, Concepción, Chile
| | - Francisco Westermeier
- Institute of Biomedical Science, FH Joanneum Gesellschaft mbH University of Applied Sciences, Eggenberger Allee 13, 8020 Graz, Austria
- Facultad de Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Pamela Silva
- Facultad de Salud, Universidad Santo Tomás, Osorno, Chile
| | - Rodrigo Gatica
- Escuela de Veterinaria, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Joana Moitinho Oliveira
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- Diabetes and Obesity Research Laboratory, IDIBAPS, Barcelona, Spain
| | - Francisco Nualart
- Centro de Microscopía Avanzada (CMA BIO-BIO), Universidad de Concepción, Concepción, Chile
| | - Ramón Gomis
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
- Diabetes and Obesity Research Laboratory, IDIBAPS, Barcelona, Spain
- Department of Endocrinology and Nutrition, Hospital Clinic, Barcelona, Spain
- Faculty of Medicine, University of Barcelona, Barcelona, Spain
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Sasaki M, Sasako T, Kubota N, Sakurai Y, Takamoto I, Kubota T, Inagi R, Seki G, Goto M, Ueki K, Nangaku M, Jomori T, Kadowaki T. Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney. Diabetes 2017. [PMID: 28630133 DOI: 10.2337/db16-1602] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs.
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Affiliation(s)
- Motohiro Sasaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
| | - Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Translational Systems Biology and Medicine Initiative, The University of Tokyo, Tokyo, Japan
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Translational Systems Biology and Medicine Initiative, The University of Tokyo, Tokyo, Japan
- Department of Clinical Nutrition Therapy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan
- Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan
- Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
| | - Yoshitaka Sakurai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Iseki Takamoto
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuya Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, Japan
- Laboratory for Metabolic Homeostasis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Reiko Inagi
- Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Moritaka Goto
- Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
| | - Kohjiro Ueki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Translational Systems Biology and Medicine Initiative, The University of Tokyo, Tokyo, Japan
- Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masaomi Nangaku
- Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahito Jomori
- Mie Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Translational Systems Biology and Medicine Initiative, The University of Tokyo, Tokyo, Japan
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42
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Alarcón S, Garrido W, Vega G, Cappelli C, Suárez R, Oyarzún C, Quezada C, San Martín R. Deficient Insulin-mediated Upregulation of the Equilibrative Nucleoside Transporter 2 Contributes to Chronically Increased Adenosine in Diabetic Glomerulopathy. Sci Rep 2017; 7:9439. [PMID: 28842605 PMCID: PMC5572683 DOI: 10.1038/s41598-017-09783-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 07/28/2017] [Indexed: 12/21/2022] Open
Abstract
Deficient insulin signaling is a key event mediating diabetic glomerulopathy. Additionally, diabetic kidney disease has been related to increased levels of adenosine. Therefore, we tested a link between insulin deficiency and dysregulated activity of the equilibrative nucleoside transporters (ENTs) responsible for controlling extracellular levels of adenosine. In ex vivo glomeruli, high D-glucose decreased nucleoside uptake mediated by ENT1 and ENT2 transporters, resulting in augmented extracellular levels of adenosine. This condition was reversed by exposure to insulin. Particularly, insulin through insulin receptor/PI3K pathway markedly upregulated ENT2 uptake activity to restores the extracellular basal level of adenosine. Using primary cultured rat podocytes as a cellular model, we found insulin was able to increase ENT2 maximal velocity of transport. Also, PI3K activity was necessary to maintain ENT2 protein levels in the long term. In glomeruli of streptozotocin-induced diabetic rats, insulin deficiency leads to decreased activity of ENT2 and chronically increased extracellular levels of adenosine. Treatment of diabetic rats with adenosine deaminase attenuated both the glomerular loss of nephrin and proteinuria. In conclusion, we evidenced ENT2 as a target of insulin signaling and sensitive to dysregulation in diabetes, leading to chronically increased extracellular adenosine levels and thereby setting conditions conducive to kidney injury.
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Affiliation(s)
- Sebastián Alarcón
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Wallys Garrido
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Génesis Vega
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Claudio Cappelli
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Raibel Suárez
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Carlos Oyarzún
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile.
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43
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Oyarzún C, Garrido W, Alarcón S, Yáñez A, Sobrevia L, Quezada C, San Martín R. Adenosine contribution to normal renal physiology and chronic kidney disease. Mol Aspects Med 2017; 55:75-89. [PMID: 28109856 DOI: 10.1016/j.mam.2017.01.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 12/12/2022]
Abstract
Adenosine is a nucleoside that is particularly interesting to many scientific and clinical communities as it has important physiological and pathophysiological roles in the kidney. The distribution of adenosine receptors has only recently been elucidated; therefore it is likely that more biological roles of this nucleoside will be unveiled in the near future. Since the discovery of the involvement of adenosine in renal vasoconstriction and regulation of local renin production, further evidence has shown that adenosine signaling is also involved in the tubuloglomerular feedback mechanism, sodium reabsorption and the adaptive response to acute insults, such as ischemia. However, the most interesting finding was the increased adenosine levels in chronic kidney diseases such as diabetic nephropathy and also in non-diabetic animal models of renal fibrosis. When adenosine is chronically increased its signaling via the adenosine receptors may change, switching to a state that induces renal damage and produces phenotypic changes in resident cells. This review discusses the physiological and pathophysiological roles of adenosine and pays special attention to the mechanisms associated with switching homeostatic nucleoside levels to increased adenosine production in kidneys affected by CKD.
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Affiliation(s)
- Carlos Oyarzún
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Wallys Garrido
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Sebastián Alarcón
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Alejandro Yáñez
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston QLD 4029, Queensland, Australia
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile.
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44
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Katsoulieris EN, Drossopoulou GI, Kotsopoulou ES, Vlahakos DV, Lianos EA, Tsilibary EC. High Glucose Impairs Insulin Signaling in the Glomerulus: An In Vitro and Ex Vivo Approach. PLoS One 2016; 11:e0158873. [PMID: 27434075 PMCID: PMC4951020 DOI: 10.1371/journal.pone.0158873] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 06/23/2016] [Indexed: 01/14/2023] Open
Abstract
Objective Chronic hyperglycaemia, as seen in type II diabetes, results in both morphological and functional impairments of podocytes in the kidney. We investigated the effects of high glucose (HG) on the insulin signaling pathway, focusing on cell survival and apoptotic markers, in immortalized human glomerular cells (HGEC; podocytes) and isolated glomeruli from healthy rats. Methods and Findings HGEC and isolated glomeruli were cultured for various time intervals under HG concentrations in the presence or absence of insulin. Our findings indicated that exposure of HGEC to HG led to downregulation of all insulin signaling markers tested (IR, p-IR, IRS-1, p-Akt, p-Fox01,03), as well as to increased sensitivity to apoptosis (as seen by increased PARP cleavage, Casp3 activation and DNA fragmentation). Short insulin pulse caused upregulation of insulin signaling markers (IR, p-IR, p-Akt, p-Fox01,03) in a greater extent in normoglycaemic cells compared to hyperglycaemic cells and for the case of p-Akt, in a PI3K-dependent manner. IRS-1 phosphorylation of HG-treated podocytes was negatively regulated, favoring serine versus tyrosine residues. Prolonged insulin treatment caused a significant decrease of IR levels, while alterations in glucose concentrations for various time intervals demonstrated changes of IR, p-IR and p-Akt levels, suggesting that the IR signaling pathway is regulated by glucose levels. Finally, HG exerted similar effects in isolated glomeruli. Conclusions These results suggest that HG compromises the insulin signaling pathway in the glomerulus, promoting a proapoptotic environment, with a possible critical step for this malfunction lying at the level of IRS-1 phosphorylation; thus we herein demonstrate glomerular insulin signaling as another target for investigation for the prevention and/ or treatment of diabetic nephropathy.
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Affiliation(s)
- Elias N. Katsoulieris
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
| | - Garyfalia I. Drossopoulou
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
- * E-mail: (GID); (ECT)
| | - Eleni S. Kotsopoulou
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
| | - Dimitrios V. Vlahakos
- 2nd Department of Propaedeutic Medicine, Attikon University Hospital, Athens, Greece
| | - Elias A. Lianos
- Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| | - Effie C. Tsilibary
- Institute of Biosciences and Applications, National Center for Scientific Research ‘Demokritos’, Athens, Greece
- * E-mail: (GID); (ECT)
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45
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Pandey G, Shankar K, Makhija E, Gaikwad A, Ecelbarger C, Mandhani A, Srivastava A, Tiwari S. Reduced Insulin Receptor Expression Enhances Proximal Tubule Gluconeogenesis. J Cell Biochem 2016; 118:276-285. [PMID: 27322100 DOI: 10.1002/jcb.25632] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/16/2016] [Indexed: 12/18/2022]
Abstract
Reduced insulin receptor protein levels have been reported in the kidney cortex from diabetic humans and animals. We recently reported that, targeted deletion of insulin receptor (IR) from proximal tubules (PT) resulted in hyperglycemia in non-obese mice. To elucidate the mechanism, we examined human proximal tubule cells (hPTC) and C57BL/6 mice fed with high-fat diet (HFD, 60% fat for 20 weeks). Immunoblotting revealed a significantly lower protein level of IR in HFD compare to normal chow diet (NCD). Furthermore, a blunted rise in p-AKT308 levels in the kidney cortex of HFD mice was observed in response to acute insulin (0.75 IU/kg body weight, i.p) relative to NCD n = 8/group, P < 0.05). Moreover, we found significantly higher transcript levels of phosphoenolpyruvate carboxykinase (PEPCK, a key gluconeogenic enzyme) in the kidney cortex from HFD, relative to mice on NCD. The higher level of PEPCK in HFD was confirmed by immunoblotting. However, no significant differences were observed in cortical glucose-6-phosphatase (G6Pase) or fructose-1,6, bisphosphosphatase (FBPase) enzyme transcript levels. Furthermore, we demonstrated insulin inhibited glucose production in hPTC treated with cyclic AMP and dexamethasone (cAMP/DEXA) to stimulate gluconeogenesis. Transcript levels of the gluconeogenic enzyme PEPCK were significantly increased in cAMP/DEXA-stimulated hPTC cells (n = 3, P < 0.05), and insulin attenuated this upregulation Furthermore, the effect of insulin on cAMP/DEXA-induced gluconeogenesis and PEPCK induction was significantly attenuated in IR (siRNA) silenced hPTC (n = 3, P < 0.05). Overall the above data indicate a direct role for IR expression as a determinant of PT-gluconeogenesis. Thus reduced insulin signaling of the proximal tubule may contribute to hyperglycemia in the metabolic syndrome via elevated gluconeogenesis. J. Cell. Biochem. 118: 276-285, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Gaurav Pandey
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India
| | | | - Ekta Makhija
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India
| | | | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, District of Columbia
| | | | | | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, SGPGIMS, Lucknow, 226014, India.,Department of Medicine, Georgetown University, Washington, District of Columbia
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46
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Bertinat R, Westermeier F, Silva P, Shi J, Nualart F, Li X, Yáñez AJ. Anti-Diabetic Agent Sodium Tungstate Induces the Secretion of Pro- and Anti-Inflammatory Cytokines by Human Kidney Cells. J Cell Physiol 2016; 232:355-362. [PMID: 27186953 DOI: 10.1002/jcp.25429] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/16/2016] [Indexed: 02/04/2023]
Abstract
Diabetic kidney disease (DKD) is the major cause of end stage renal disease. Sodium tungstate (NaW) exerts anti-diabetic and immunomodulatory activities in diabetic animal models. Here, we used primary cultures of renal proximal tubule epithelial cells derived from type-2-diabetic (D-RPTEC) and non-diabetic (N-RPTEC) subjects as in vitro models to study the effects of NaW on cytokine secretion, as these factors participate in intercellular regulation of inflammation, cell growth and death, differentiation, angiogenesis, development, and repair, all processes that are dysregulated during DKD. In basal conditions, D-RPTEC cells secreted higher levels of prototypical pro-inflammatory IL-6, IL-8, and MCP-1 than N-RPTEC cells, in agreement with their diabetic phenotype. Unexpectedly, NaW further induced IL-6, IL-8, and MCP-1 secretion in both N- and D-RPTEC, together with lower levels of IL-1 RA, IL-4, IL-10, and GM-CSF, suggesting that it may contribute to the extent of renal damage/repair during DKD. Besides, NaW induced the accumulation of IκBα, the main inhibitor protein of one major pathway involved in cytokine production, suggesting further anti-inflammatory effect in the long-term. A better understanding of the mechanisms involved in the interplay between the anti-diabetic and immunomodulatory properties of NaW will facilitate future studies about its clinical relevance. J. Cell. Physiol. 232: 355-362, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Romina Bertinat
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile. .,Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile. .,Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Francisco Westermeier
- Facultad de Ciencias Químicas y Farmacéuticas and Facultad de Medicina, Centro Avanzado de Enfermedades Crónicas (ACCDiS), Universidad de Chile, Santiago, Chile.,Facultad de Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Pamela Silva
- Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
| | - Jie Shi
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Francisco Nualart
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile
| | - Xuhang Li
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alejandro J Yáñez
- Centro de Microscopía Avanzada, CMA-Bío Bío, Universidad de Concepción, Concepción, Chile. .,Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile.
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47
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Selective Insulin Resistance in the Kidney. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5825170. [PMID: 27247938 PMCID: PMC4876201 DOI: 10.1155/2016/5825170] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 04/04/2016] [Accepted: 04/07/2016] [Indexed: 12/12/2022]
Abstract
Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule.
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48
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Bertinat R, Silva P, Mann E, Li X, Nualart F, Yáñez AJ. In vivo sodium tungstate treatment prevents E-cadherin loss induced by diabetic serum in HK-2 cell line. J Cell Physiol 2015; 230:2437-46. [PMID: 25728412 DOI: 10.1002/jcp.24974] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Accepted: 02/24/2015] [Indexed: 01/06/2023]
Abstract
Diabetic nephropathy (DN) is characterized by interstitial inflammation and fibrosis, which is the result of chronic accumulation of extracellular matrix produced by activated fibroblasts in the renal tubulointerstitium. Renal proximal tubular epithelial cells (PTECs), through the process of epithelial-to-mesenchymal transition (EMT), are the source of fibroblasts within the interstitial space, and loss of E-cadherin has shown to be one of the earliest steps in this event. Here, we studied the effect of the anti-diabetic agent sodium tungstate (NaW) in the loss of E-cadherin induced by transforming growth factor (TGF) β-1, the best-characterized in vitro EMT promoter, and serum from untreated or NaW-treated diabetic rats in HK-2 cell line, a model of human kidney PTEC. Our results showed that both TGFβ-1 and serum from diabetic rat induced a similar reduction in E-cadherin expression. However, E-cadherin loss induced by TGFβ-1 was not reversed by NaW, whereas sera from NaW-treated rats were able to protect HK-2 cells. Searching for soluble mediators of NaW effect, we compared secretion of TGFβ isoforms and vascular endothelial growth factor (VEGF)-A, which have opposite actions on EMT. One millimolar NaW alone reduced secretion of both TGFβ-1 and -2, and stimulated secretion of VEGF-A after 48 h. However, these patterns of secretion were not observed after diabetic rat serum treatment, suggesting that protection from E-cadherin loss by serum from NaW-treated diabetic rats originates from an indirect rather than a direct effect of this salt on HK-2 cells, via a mechanism independent of TGFβ and VEGF-A functions.
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Affiliation(s)
- Romina Bertinat
- Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile.,Centro de Microscopía Avanzada (CMA)-Bío Bío, Universidad de Concepción, Concepción, Chile
| | - Pamela Silva
- Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile
| | - Elizabeth Mann
- Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xuhang Li
- Division of Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Francisco Nualart
- Centro de Microscopía Avanzada (CMA)-Bío Bío, Universidad de Concepción, Concepción, Chile
| | - Alejandro J Yáñez
- Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile.,Centro de Microscopía Avanzada (CMA)-Bío Bío, Universidad de Concepción, Concepción, Chile
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49
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Nakamura M, Satoh N, Suzuki M, Kume H, Homma Y, Seki G, Horita S. Stimulatory effect of insulin on renal proximal tubule sodium transport is preserved in type 2 diabetes with nephropathy. Biochem Biophys Res Commun 2015; 461:154-8. [DOI: 10.1016/j.bbrc.2015.04.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 04/01/2015] [Indexed: 11/16/2022]
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50
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Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway. J Nutr Biochem 2015; 26:596-606. [PMID: 25724107 DOI: 10.1016/j.jnutbio.2014.12.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 11/26/2014] [Accepted: 12/10/2014] [Indexed: 01/01/2023]
Abstract
Sulforaphane (SFN), the bioactive component of cruciferous vegetables, is a potent indirect antioxidant. Oxidative stress and activation of glycogen synthase kinase 3beta (GSK3β) are two major contributors to the pathogenesis of diabetic nephropathy (DN). Here, we investigated whether and how SFN affected GSK3β in experimental models of DN in vivo and in vitro. SFN treatment obviously prevented the increase in urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Simultaneously, the level of 8-oxo-deoxyguanosine, an indicator of oxidative damage, was markedly lowered in SFN-treated diabetic rats, together with a significant reduction in activity of the GSK-3β/Fyn axis and an evident activation of Nrf2 signaling. Similarly, antifibrotic effects of SFN, parallel to enhanced inhibitory Ser9-phosphorylation of GSK3β and Fyn/Nrf2 nuclear export/import, were observed in the cultured rat mesangial cells (RMC) exposed to high glucose. The salutary effects of SFN on high-glucose-stimulated RMC were abolished by overexpression of GSK3β while being rescued by lithium chloride, a well-known GSK3β inhibitor. Taken together, our findings suggested that SFN ameliorated experimental diabetic nephropathy, at least in part, via GSK3β/Fyn/Nrf2 signaling pathway.
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