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1
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Zhu M, Yi X, Song S, Yang H, Yu J, Xu C. Principle role of the (pro)renin receptor system in cardiovascular and metabolic diseases: An update. Cell Signal 2024; 124:111417. [PMID: 39321906 DOI: 10.1016/j.cellsig.2024.111417] [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: 06/24/2024] [Revised: 09/07/2024] [Accepted: 09/15/2024] [Indexed: 09/27/2024]
Abstract
(Pro)renin receptor (PRR), along with its soluble form, sPRR, functions not only as a crucial activator of the local renin-angiotensin system but also engages with and activates various angiotensin II-independent signaling pathways, thus playing complex and significant roles in numerous physiological and pathophysiological processes, including cardiovascular and metabolic disorders. This article reviews current knowledge on the intracellular partners of the PRR system and explores its physiological and pathophysiological impacts on cardiovascular diseases as well as conditions related to glucose and lipid metabolism, such as hypertension, heart disease, liver disease, diabetes, and diabetic complications. Targeting the PRR system could emerge as a promising therapeutic strategy for treating these conditions. Elevated levels of circulating sPRR might indicate the severity of these diseases, potentially serving as a biomarker for diagnosis and prognosis in clinical settings. A comprehensive understanding of the functions and regulatory mechanisms of the PRR system could facilitate the development of novel therapeutic approaches for the prevention and management of cardiovascular and metabolic diseases.
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Affiliation(s)
- Mengzhi Zhu
- College of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Xiaoli Yi
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Shanshan Song
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Huiru Yang
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang 330004, China
| | - Jun Yu
- Center for Metabolic Disease Research and Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Chuanming Xu
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
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2
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Guo B, Li QY, Liu XJ, Luo GH, Wu YJ, Nie J. Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link. Eur J Neurosci 2024; 59:2577-2595. [PMID: 38419188 DOI: 10.1111/ejn.16286] [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: 12/01/2023] [Revised: 02/01/2024] [Accepted: 02/02/2024] [Indexed: 03/02/2024]
Abstract
Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v-ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v-ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and β-amyloid (Aβ). In DM, v-ATPase is involved in the regulation of glucose metabolism and IR. v-ATPase is closely related to glycolysis. On the one hand, v-ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK-1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v-ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v-ATPase can also regulate free fatty acids, thereby improving IR. In AD, v-ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aβ by affecting the production and degradation of Aβ. Therefore, v-ATPase may be the bridge between DM and AD.
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Affiliation(s)
- Bin Guo
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Qi-Ye Li
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Xue-Jia Liu
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Guo-Hui Luo
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ya-Juan Wu
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
| | - Jing Nie
- Key Laboratory of Basic Pharmacology of the Ministry of Education and Joint International Research Laboratory of Ethnomedicine of the Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China
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3
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Funke-Kaiser H, Unger T. The (pro)renin receptor as a pharmacological target in cardiorenal diseaes. Hypertens Res 2023; 46:2527-2534. [PMID: 37667044 DOI: 10.1038/s41440-023-01424-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/02/2023] [Accepted: 08/14/2023] [Indexed: 09/06/2023]
Abstract
The (pro)renin receptor ((P)RR) is not only a member of the renin-angiotensin system (RAS) but also exerts several RAS-independent functions due to its multiple signal transductions pathways. In this mini-review, we shortly discuss the molecular functions of this receptor and its pathophysiological significance with a focus on cardiorenal diseases. Finally, we provide a short summary regarding a drug discovery and drug development program on small molecule-based renin/ prorenin receptor blockers (RERBs).
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Affiliation(s)
| | - Thomas Unger
- CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
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Hejazian SM, Ardalan M, Hosseiniyan Khatibi SM, Rahbar Saadat Y, Barzegari A, Gueguen V, Meddahi-Pellé A, Anagnostou F, Zununi Vahed S, Pavon-Djavid G. Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies. J Cell Physiol 2023; 238:2206-2227. [PMID: 37659096 DOI: 10.1002/jcp.31110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/25/2023] [Accepted: 08/14/2023] [Indexed: 09/04/2023]
Abstract
Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies are classified as kidney diseases caused by podocyte damage. Different genetic and environmental risk factors can cause podocyte damage and death. Recent evidence shows that mitochondrial dysfunction also contributes to podocyte damage. Understanding alterations in mitochondrial metabolism and function in podocytopathies and whether altered mitochondrial homeostasis/dynamics is a cause or effect of podocyte damage are issues that need in-depth studies. This review highlights the roles of mitochondria and their bioenergetics in podocytes. Then, factors/signalings that regulate mitochondria in podocytes are discussed. After that, the role of mitochondrial dysfunction is reviewed in podocyte injury and the development of different podocytopathies. Finally, the mitochondrial therapeutic targets are considered.
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Affiliation(s)
| | | | | | | | - Abolfazl Barzegari
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Virginie Gueguen
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Anne Meddahi-Pellé
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
| | - Fani Anagnostou
- Université de Paris, CNRS UMR 7052 INSERM U1271, B3OA, Paris, France
| | | | - Graciela Pavon-Djavid
- Université Sorbonne Paris Nord, INSERM U1148, Laboratory for Vascular Translational Science, Cardiovascular Bioengineering, Villetaneuse, France
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5
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Mathieu NM, Fekete EM, Muskus PC, Brozoski DT, Lu KT, Wackman KK, Gomez J, Fang S, Reho JJ, Grobe CC, Vazirabad I, Mouradian GC, Hodges MR, Segar JL, Grobe JL, Sigmund CD, Nakagawa P. Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension. FUNCTION 2023; 4:zqad043. [PMID: 37609445 PMCID: PMC10440998 DOI: 10.1093/function/zqad043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/31/2023] [Accepted: 08/02/2023] [Indexed: 08/24/2023] Open
Abstract
Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin-angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract.
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Affiliation(s)
- Natalia M Mathieu
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Eva M Fekete
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Patricia C Muskus
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Daniel T Brozoski
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ko-Ting Lu
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Kelsey K Wackman
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Javier Gomez
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Shi Fang
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - John J Reho
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Connie C Grobe
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ibrahim Vazirabad
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Gary C Mouradian
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Matthew R Hodges
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Jeffrey L Segar
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Justin L Grobe
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Curt D Sigmund
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Pablo Nakagawa
- Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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6
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Bhatia D, Choi ME. Autophagy and mitophagy: physiological implications in kidney inflammation and diseases. Am J Physiol Renal Physiol 2023; 325:F1-F21. [PMID: 37167272 PMCID: PMC10292977 DOI: 10.1152/ajprenal.00012.2023] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/25/2023] [Accepted: 05/09/2023] [Indexed: 05/13/2023] Open
Abstract
Autophagy is a ubiquitous intracellular cytoprotective quality control program that maintains cellular homeostasis by recycling superfluous cytoplasmic components (lipid droplets, protein, or glycogen aggregates) and invading pathogens. Mitophagy is a selective form of autophagy that by recycling damaged mitochondrial material, which can extracellularly act as damage-associated molecular patterns, prevents their release. Autophagy and mitophagy are indispensable for the maintenance of kidney homeostasis and exert crucial functions during both physiological and disease conditions. Impaired autophagy and mitophagy can negatively impact the pathophysiological state and promote its progression. Autophagy helps in maintaining structural integrity of the kidney. Mitophagy-mediated mitochondrial quality control is explicitly critical for regulating cellular homeostasis in the kidney. Both autophagy and mitophagy attenuate inflammatory responses in the kidney. An accumulating body of evidence highlights that persistent kidney injury-induced oxidative stress can contribute to dysregulated autophagic and mitophagic responses and cell death. Autophagy and mitophagy also communicate with programmed cell death pathways (apoptosis and necroptosis) and play important roles in cell survival by preventing nutrient deprivation and regulating oxidative stress. Autophagy and mitophagy are activated in the kidney after acute injury. However, their aberrant hyperactivation can be deleterious and cause tissue damage. The findings on the functions of autophagy and mitophagy in various models of chronic kidney disease are heterogeneous and cell type- and context-specific dependent. In this review, we discuss the roles of autophagy and mitophagy in the kidney in regulating inflammatory responses and during various pathological manifestations.
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Affiliation(s)
- Divya Bhatia
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, United States
| | - Mary E Choi
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, United States
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7
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Vöing K, Michgehl U, Mertens ND, Picciotto C, Maywald ML, Goretzko J, Waimann S, Gilhaus K, Rogg M, Schell C, Klingauf J, Tsytsyura Y, Hansen U, van Marck V, Edinger AL, Vollenbröker B, Rescher U, Braun DA, George B, Weide T, Pavenstädt H. Disruption of the Rab7-Dependent Final Common Pathway of Endosomal and Autophagic Processing Results in a Severe Podocytopathy. J Am Soc Nephrol 2023; 34:1191-1206. [PMID: 37022133 PMCID: PMC10356157 DOI: 10.1681/asn.0000000000000126] [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: 10/26/2022] [Accepted: 03/03/2023] [Indexed: 04/07/2023] Open
Abstract
SIGNIFICANCE STATEMENT Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve our understanding on how disturbances of these trafficking pathways are linked to podocyte depletion and slit diaphragm (SD) injury, the authors explored the role of the small GTPase Rab7, which is linked to endosomal, lysosomal, and autophagic pathways, using as model systems mice and Drosophila with podocyte-specific or nephrocyte-specific loss of Rab7, and a human podocyte cell line depleted for Rab7. Their findings point to maturation and fusion events during endolysosomal and autophagic maturation as key processes for podocyte homeostasis and function and identify altered lysosomal pH values as a putative novel mechanism for podocytopathies. BACKGROUND Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood. METHODS To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab7. RESULTS Depletion of Rab7 in mice, Drosophila , and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, Rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro , Rab7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins. CONCLUSIONS Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease.
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Affiliation(s)
- Kristin Vöing
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Ulf Michgehl
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Nils David Mertens
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Cara Picciotto
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Mee-Ling Maywald
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Jonas Goretzko
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Muenster, Germany
| | - Sofie Waimann
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Kevin Gilhaus
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Manuel Rogg
- Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Christoph Schell
- Institute of Surgical Pathology, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany
- Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
| | - Jürgen Klingauf
- Institute of Medical Physics and Biophysics, University of Muenster, Muenster, Germany
| | - Yaroslav Tsytsyura
- Institute of Medical Physics and Biophysics, University of Muenster, Muenster, Germany
| | - Uwe Hansen
- Institute for Musculoskeletal Medicine (IMM), University of Muenster, Muenster, Germany
| | - Veerle van Marck
- Department of Pathology, University Hospital Muenster Muenster, Germany
| | - Aimee L. Edinger
- Department of Developmental & Cell Biology, University of California, Irvine, California
| | - Beate Vollenbröker
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Ursula Rescher
- Research Group Regulatory Mechanisms of Inflammation, Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Muenster, Muenster, Germany
| | - Daniela Anne Braun
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Britta George
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Thomas Weide
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
| | - Hermann Pavenstädt
- Department of Internal Medicine and Nephrology, University Hospital of Münster, Medical Clinic D, Munster, Germany
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8
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Ruby M, Gifford CC, Pandey R, Raj VS, Sabbisetti VS, Ajay AK. Autophagy as a Therapeutic Target for Chronic Kidney Disease and the Roles of TGF-β1 in Autophagy and Kidney Fibrosis. Cells 2023; 12:412. [PMID: 36766754 PMCID: PMC9913737 DOI: 10.3390/cells12030412] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
Autophagy is a lysosomal protein degradation system that eliminates cytoplasmic components such as protein aggregates, damaged organelles, and even invading pathogens. Autophagy is an evolutionarily conserved homoeostatic strategy for cell survival in stressful conditions and has been linked to a variety of biological processes and disorders. It is vital for the homeostasis and survival of renal cells such as podocytes and tubular epithelial cells, as well as immune cells in the healthy kidney. Autophagy activation protects renal cells under stressed conditions, whereas autophagy deficiency increases the vulnerability of the kidney to injury, resulting in several aberrant processes that ultimately lead to renal failure. Renal fibrosis is a condition that, if chronic, will progress to end-stage kidney disease, which at this point is incurable. Chronic Kidney Disease (CKD) is linked to significant alterations in cell signaling such as the activation of the pleiotropic cytokine transforming growth factor-β1 (TGF-β1). While the expression of TGF-β1 can promote fibrogenesis, it can also activate autophagy, which suppresses renal tubulointerstitial fibrosis. Autophagy has a complex variety of impacts depending on the context, cell types, and pathological circumstances, and can be profibrotic or antifibrotic. Induction of autophagy in tubular cells, particularly in the proximal tubular epithelial cells (PTECs) protects cells against stresses such as proteinuria-induced apoptosis and ischemia-induced acute kidney injury (AKI), whereas the loss of autophagy in renal cells scores a significant increase in sensitivity to several renal diseases. In this review, we discuss new findings that emphasize the various functions of TGF-β1 in producing not just renal fibrosis but also the beneficial TGF-β1 signaling mechanisms in autophagy.
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Affiliation(s)
- Miss Ruby
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - Cody C. Gifford
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - RamendraPati Pandey
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - V. Samuel Raj
- Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi-NCR, Rajiv Gandhi Education City, Sonepat 131029, Haryana, India
| | - Venkata S. Sabbisetti
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Amrendra K. Ajay
- Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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9
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Funke-Kaiser H, Unger T. The (Pro)renin Receptor - A Regulatory Nodal Point in Disease Networks. Curr Drug Targets 2023; 24:1093-1098. [PMID: 37885110 DOI: 10.2174/0113894501250617231016052930] [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: 02/23/2023] [Revised: 06/27/2023] [Accepted: 09/15/2023] [Indexed: 10/28/2023]
Abstract
Experimental inhibition of the (pro)renin receptor [(P)RR] is a promising therapeutic strategy in different disease models ranging from cardiorenal to oncological entities. Here, we briefly review the direct protein-protein interaction partners of the (P)RR and the plethora of distinct diseases in which the (P)RR is involved. The first structural work on the (P)RR using AlphaFold, which was recently published by Ebihara et al., is the center of this mini-review since it can mechanistically link the protein-protein interaction level with the pathophysiological level. More detailed insights into the 3D structure of the (P)RR and its interaction domains might guide drug discovery on this novel target. Finally, antibody- and small molecule-based approaches to inhibit the (P)RR are shortly discussed.
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Affiliation(s)
| | - Thomas Unger
- CARIM - School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
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10
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Sato S, Hirose T, Ohba K, Watanabe F, Watanabe T, Minato K, Endo A, Ito H, Mori T, Takahashi K. (Pro)renin receptor and insulin signaling regulate cell proliferation in MCF-7 breast cancer cells. J Biochem 2022; 172:355-363. [PMID: 36071571 DOI: 10.1093/jb/mvac072] [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: 10/29/2021] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
(Pro)renin receptor [(P)RR] is related to both the renin-angiotensin system and V-ATPase with various functions including stimulation of cell proliferation. (P)RR is implicated in the pathophysiology of diabetes mellitus and cancer. Hyperinsulinemia is observed in obesity-related breast cancer. However, the relationship between (P)RR and insulin has not been clarified. We have therefore studied the effect of insulin on (P)RR expression, cell viability, and AKT phosphorylation under the conditions with and without (P)RR knockdown. Effects of insulin were studied in a human breast cancer cell line, MCF-7. Cell proliferation assay was performed by WST-8 assay. (P)RR expression was suppressed by (P)RR-specific siRNAs. The treated cells were analyzed by western blotting and real-time quantitative PCR analysis. Insulin stimulated proliferation of MCF-7 cells and increased (P)RR protein expression, but not (P)RR mRNA levels. Moreover, autophagy flux was suppressed by insulin. Suppression of (P)RR expression reduced cell number of MCF-7 cells and AKT phosphorylation significantly in both the presence and the absence of insulin, indicating that (P)RR is important for cell viability and AKT phosphorylation. In conclusion, insulin upregulates the level of (P)RR protein, which is important for cell viability, proliferation, AKT phosphorylation, and autophagy in breast cancer cells.
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Affiliation(s)
- Shigemitsu Sato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuo Hirose
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.,Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Koji Ohba
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Fumihiko Watanabe
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoki Watanabe
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuya Minato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akari Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Hiroki Ito
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.,Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
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11
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Nichols K, Yiannikouris F. The Role of (Pro)Renin Receptor in the Metabolic Syndrome. Curr Hypertens Rev 2022; 18:117-124. [PMID: 35170416 DOI: 10.2174/1573402118666220216104816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 01/27/2023]
Abstract
The prorenin receptor (PRR) is a complex multi-functional single transmembrane protein receptor that is ubiquitously expressed in organs and tissues throughout the body. PRR is involved in different cellular mechanisms that comprise the generation of Angiotensin II, the activation of Wnt/β-catenin signaling, the stimulation of ERK 1/2 pathway, and the proper functioning of the vacuolar H+-ATPase. Evidence supports the role of PRR and its soluble form, sPRR, in the classical features of the metabolic syndrome, including obesity, hypertension, diabetes, and disruption of lipid homeostasis. This review summarizes our current knowledge and highlights new advances in the pathophysiological function of PRR and sPRR in adipogenesis, adipocyte differentiation, lipolysis, glucose and insulin resistance, lipid homeostasis, energy metabolism, and blood pressure regulation.
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Affiliation(s)
- Kellea Nichols
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Frederique Yiannikouris
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
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12
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Podestà MA, Faravelli I, Ponticelli C. Autophagy in lupus nephritis: A delicate balance between regulation and disease. Clin Exp Rheumatol 2022; 21:103132. [PMID: 35690243 DOI: 10.1016/j.autrev.2022.103132] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/07/2022] [Indexed: 11/02/2022]
Abstract
Autophagy is a highly regulated process wherein an unwanted cargo of damaged and dysfunctional cytoplasmic components is removed, delivered to lysosomes for degradation, and released back into the cytoplasm. Accumulating evidence suggests an important role of autophagy in the pathophysiology of systemic lupus erythematosus, with profound effects on both innate and adaptive immunity. Autophagy downregulation results in the inhibition of antigen presenting cells, reduced release of neutrophil extracellular traps and decreased activation of effector T and B cells, leading to reduced autoantibody production and attenuated type 1 interferon signaling. However, defective autophagy may accelerate the production of other inflammatory cytokines and reduce the clearance of apoptotic cells, promoting lupus development. In addition, autophagy dysfunction can concur to the pathogenesis of kidney injury in lupus nephritis. Autophagy is a pivotal mechanism to maintain podocyte integrity and endothelial cell survival. Several animal models have demonstrated that defective autophagy leads to podocyte injury and can promote an endothelial pro-inflammatory and atherogenic phenotype. Moreover, autophagy is a key homeostatic regulator of renal tubular cells, and recent evidence has pointed out that chronic autophagy deficiency may accelerate kidney fibrosis. Targeting autophagy may theoretically improve lupus nephritis outcomes, but novel, non-invasive methods to measure and monitor autophagic activity are urgently needed. In addition, the extent and timing of autophagy inhibition still require additional studies before clinical translation may be attempted. In this review, we will also discuss the effect of several clinically available drugs that can regulate the autophagic flux and their effect in lupus nephritis patients.
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Affiliation(s)
- Manuel Alfredo Podestà
- Renal Division, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy.
| | - Irene Faravelli
- Neuroscience Section, Dino Ferrari Centre, Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy
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13
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Li L, Cui YJ, Liu Y, Li HX, Su YD, Li SN, Wang LL, Zhao YW, Wang SX, Yan F, Dong B. ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation. Cell Death Dis 2022; 8:161. [PMID: 35379787 PMCID: PMC8980069 DOI: 10.1038/s41420-022-00967-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/09/2022] [Accepted: 03/21/2022] [Indexed: 11/24/2022]
Abstract
Moderate autophagy can remove damaged proteins and organelles. In some inflammatory diseases, autophagy plays a protective role by inhibiting the NOD-like receptor family pyrin domain containing 3(NLRP3). (Pro)renin receptor (PRR, or ATP6AP2) is a critical component of the V-ATPase required for autophagy. It remains controversial about ATP6AP2 in the pathological process. The impact of ATP6AP2 on NLRP3 inflammasome and autophagic flux remains unknown under pressure overload stress. This research explores the potential link between ATP6AP2, autophagic flux, and NLRP3. There was upregulation of ATP6AP2 from 5-day post-TAC, and this expression remained at a high level until 8-weeks post-TAC in wild mice. Meanwhile, autophagic flux switched from early compensatory activation to blocking in the heart failure phase. NLRP3 activation can be seen at 8-week post-TAC. Adenovirus-mediated knockdown of ATP6AP2(shR-ATP6AP2) accelerated the progress of heart failure. After TAC was induced, shR-ATP6AP2 significantly deteriorated heart function and fibrosis compared with the shR-Scr group. Meanwhile, there was an elevated expression of NLRP3 and autophagic flux blockage. A transgenic mouse(Tg) with cardio-restricted ATP6AP2/(P)RR overexpression was constructed. Although high expression in cardiac tissue, there were no spontaneous functional abnormalities under the basal state. Cardiac function, fibrosis, hypertrophy remained identical to the control TAC group. However, SQSTM1/P62 was reduced, which indicated the relief of autophagic flux blockage. Further, Neonatal rat ventricular myocyte (NRVMs) transfected with shR-ATP6AP2 showed more susceptibility than sh-Scr NRVMs to phenylephrine-induced cell death. More reactive oxygen species (ROS) or mito-ROS accumulated in the shR-ATP6AP2 group when phenylephrine stimulation. Blocking NLRP3 activation in vivo partly rescued cardiac dysfunction and fibrosis. In conclusion, ATP6AP2 upregulation is a compensatory response to pressure overload. If not effectively compensated, it compromises autophagic flux, leads to dysfunctional mitochondria accumulation, further produces ROS to activate NLRP3, eventually accelerates heart failure.
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Affiliation(s)
- Lei Li
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China
| | - Ya-Juan Cui
- Department of Cardiology, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, 250012, Jinan, China
| | - Yu Liu
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China
| | - Hui-Xin Li
- Shandong University of Traditional Chinese Medicine, 250012, Jinan, China
| | - Yu-Dong Su
- Shandong University of Traditional Chinese Medicine, 250012, Jinan, China
| | - Sheng-Nan Li
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China
| | - Lan-Lan Wang
- Department of Cardiology, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, 250012, Jinan, China
| | - Yue-Wen Zhao
- Department of Cardiology, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, 250012, Jinan, China
| | - Shuang-Xi Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China
| | - Feng Yan
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China. .,Department of Emergency Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China.
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 250012, Jinan, China. .,Department of Cardiology, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, 250012, Jinan, China.
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14
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Liu WC, Chuang HC, Chou CL, Lee YH, Chiu YJ, Wang YL, Chiu HW. Cigarette Smoke Exposure Increases Glucose-6-phosphate Dehydrogenase, Autophagy, Fibrosis, and Senescence in Kidney Cells In Vitro and In Vivo. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5696686. [PMID: 35387262 PMCID: PMC8977288 DOI: 10.1155/2022/5696686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022]
Abstract
Cigarette smoke (CS) is a risk factor for chronic obstructive pulmonary disease. We attempted to investigate fully the possible effects of CS on kidney cells. We found that the viability of a human kidney proximal tubular epithelial cell line (HK-2 cells) was decreased after treatment with CS extract (CSE). In particular, the effects of CSE at low concentrations did not change the expression of apoptosis and necrosis. Furthermore, CSE increased autophagy- and fibrosis-related proteins in HK-2 cells. Senescence-related proteins and the senescence-associated secretory phenotype (SASP) increased after HK-2 cells were treated with CSE. In addition, both RNA sequencing and gene set enrichment analysis data revealed that glucose-6-phosphate dehydrogenase (G6PD) in the reactive oxygen species (ROS) pathway is responsible for the changes in CSE-treated HK-2 cells. CSE increased G6PD expression and its activity. Moreover, the inhibition of G6PD activity increased senescence in HK-2 cells. The inhibition of autophagy reinforced senescence in the CSE-treated cells. In a mouse model of CS exposure, CS caused kidney damage, including tubular injury and glomerulosclerosis. CS increased fibrosis, autophagy, and G6PD expression in kidney tissue sections. In conclusion, CS induced G6PD expression, autophagy, fibrosis, and senescence in kidney cells. G6PD has a protective role in CS-induced nephrotoxicity.
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Affiliation(s)
- Wen-Chih Liu
- Division of Nephrology, Department of Internal Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan
- Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Chu-Lin Chou
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
| | - Yu-Hsuan Lee
- Department of Cosmeceutics, China Medical University, Taichung, Taiwan
| | - Yu-Jhe Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yung-Li Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hui-Wen Chiu
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
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15
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Xu C, Liu C, Xiong J, Yu J. Cardiovascular aspects of the (pro)renin receptor: Function and significance. FASEB J 2022; 36:e22237. [PMID: 35226776 DOI: 10.1096/fj.202101649rrr] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular diseases (CVDs), including all types of disorders related to the heart or blood vessels, are the major public health problems and the leading causes of mortality globally. (Pro)renin receptor (PRR), a single transmembrane protein, is present in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. PRR plays an essential role in cardiovascular homeostasis by regulating the renin-angiotensin system and several intracellular signals such as mitogen-activated protein kinase signaling and wnt/β-catenin signaling in various cardiovascular cells. This review discusses the current evidence for the pathophysiological roles of the cardiac and vascular PRR. Activation of PRR in cardiomyocytes may contribute to myocardial ischemia/reperfusion injury, cardiac hypertrophy, diabetic or alcoholic cardiomyopathy, salt-induced heart damage, and heart failure. Activation of PRR promotes vascular smooth muscle cell proliferation, endothelial cell dysfunction, neovascularization, and the progress of vascular diseases. In addition, phenotypes of animals transgenic for PRR and the hypertensive actions of PRR in the brain and kidney and the soluble PRR are also discussed. Targeting PRR in local tissues may offer benefits for patients with CVDs, including heart injury, atherosclerosis, and hypertension.
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Affiliation(s)
- Chuanming Xu
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Chunju Liu
- Department of Clinical Laboratory, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jianhua Xiong
- Department of Cardiology, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Jun Yu
- Center for Metabolic Disease Research and Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
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16
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Ye D, Yang X, Ren L, Lu HS, Sun Y, Lin H, Tan L, Wang N, Nguyen G, Bader M, Mullick AE, Danser AHJ, Daugherty A, Jiang Y, Sun Y, Li F, Lu X. (Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice. Front Cardiovasc Med 2022; 8:725203. [PMID: 35004870 PMCID: PMC8739895 DOI: 10.3389/fcvm.2021.725203] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 11/11/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR−/− mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE−/− mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE−/− mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.
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Affiliation(s)
- Dien Ye
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, KY, United States.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Xiaofei Yang
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, Shenzhen, China
| | - Liwei Ren
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Hong S Lu
- Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Yuan Sun
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Hui Lin
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Lunbo Tan
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Na Wang
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Genevieve Nguyen
- Institut National de la Santé et de la Recherche Médicale (INSERM) and Collège de France Early Development and Pathologies Center for Interdisciplinary Research in Biology and Experimental Medicine Unit, Paris, France
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.,Institute for Biology, University of Lübeck, Lübeck, Germany.,Charité University Medicine, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
| | | | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, Rotterdam, Netherlands
| | - Alan Daugherty
- Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, KY, United States
| | - Yizhou Jiang
- Institute for Advanced Study, Shenzhen University, Shenzhen, China
| | - Yidan Sun
- Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
| | - Furong Li
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, Shenzhen, China
| | - Xifeng Lu
- Department of Pharmacology, College of Pharmacy, Shenzhen Technology University, Shenzhen, China.,Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China
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17
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Souza LA, Earley YF. (Pro)renin Receptor and Blood Pressure Regulation: A Focus on the Central Nervous System. Curr Hypertens Rev 2022; 18:101-116. [PMID: 35086455 PMCID: PMC9662243 DOI: 10.2174/1570162x20666220127105655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 09/02/2021] [Accepted: 12/06/2021] [Indexed: 01/27/2023]
Abstract
The renin-angiotensin system (RAS) is classically described as a hormonal system in which angiotensin II (Ang II) is one of the main active peptides. The action of circulating Ang II on its cognate Ang II type-1 receptor (AT1R) in circumventricular organs has important roles in regulating the autonomic nervous system, blood pressure (BP) and body fluid homeostasis, and has more recently been implicated in cardiovascular metabolism. The presence of a local or tissue RAS in various tissues, including the central nervous system (CNS), is well established. However, because the level of renin, the rate-limiting enzyme in the systemic RAS, is very low in the brain, how endogenous angiotensin peptides are generated in the CNS-the focus of this review-has been the subject of considerable debate. Notable in this context is the identification of the (pro)renin receptor (PRR) as a key component of the brain RAS in the production of Ang II in the CNS. In this review, we highlight cellular and anatomical locations of the PRR in the CNS. We also summarize studies using gain- and loss-of function approaches to elucidate the functional importance of brain PRR-mediated Ang II formation and brain RAS activation, as well as PRR-mediated Ang II-independent signaling pathways, in regulating BP. We further discuss recent developments in PRR involvement in cardiovascular and metabolic diseases and present perspectives for future directions.
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Affiliation(s)
- Lucas A.C. Souza
- Departments of Pharmacology and Physiology & Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA,Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, NV, USA
| | - Yumei Feng Earley
- Departments of Pharmacology and Physiology & Cell Biology, University of Nevada, Reno, School of Medicine, Reno, NV, USA,Center for Molecular and Cellular Signaling in the Cardiovascular System, University of Nevada, Reno, Reno, NV, USA
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18
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Culver SA, Akhtar S, Rountree-Jablin C, Keller SR, Cathro HP, Gildea JJ, Siragy HM. Knockout of Nephron ATP6AP2 Impairs Proximal Tubule Function and Prevents High-Fat Diet-Induced Obesity in Male Mice. Endocrinology 2021; 162:bqab200. [PMID: 34534267 PMCID: PMC8489432 DOI: 10.1210/endocr/bqab200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Indexed: 12/24/2022]
Abstract
ATP6AP2 expression is increased in the nephron during high-fat diet (HFD) and its knockout (ATP6AP2 KO) reduces body weight (WT) in mice. We evaluated the contribution of ATP6AP2 to urinary glucose (UG) and albumin (Ualb) handling during HFD. We hypothesized that nephron ATP6AP2 KO increases UG and Ualb and minimizes HFD-induced obesity. Eight-week-old male C57BL/6J mice with inducible nephron-specific ATP6AP2 KO and noninduced controls were fed either normal diet (ND, 12% kcal fat) or HFD (45% kcal fat) for 6 months. ATP6AP2 KO mice on ND had 20% (P < 0.01) lower WT compared with controls. HFD-fed mice had 41% (P < 0.05) greater WT than ND-fed control mice. In contrast, ATP6AP2 KO abrogated the increase in WT induced by HFD by 40% (P < 0.05). Mice on HFD had less caloric intake compared with ND controls (P < 0.01). There were no significant differences in metabolic rate between all groups. UG and Ualb was significantly increased in ATP6AP2 KO mice on both ND and HFD. ATP6AP2 KO showed greater levels of proximal tubule apoptosis and histologic evidence of proximal tubule injury. In conclusion, our results demonstrate that nephron-specific ATP6AP2 KO is associated with glucosuria and albuminuria, most likely secondary to renal proximal tubule injury and/or dysfunction. Urinary loss of nutrients may have contributed to the reduced WT of knockout mice on ND and lack of WT gain in response to HFD. Future investigation should elucidate the mechanisms by which loss of renal ATP6AP2 causes proximal tubule injury and dysfunction.
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Affiliation(s)
- Silas A Culver
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Safia Akhtar
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Callie Rountree-Jablin
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Susanna R Keller
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Helen P Cathro
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - John J Gildea
- Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Helmy M Siragy
- Division of Endocrinology, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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19
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Kashio-Yokota Y, Sato S, Hirose T, Watanabe T, Endo A, Watanabe F, Endo M, Ohba K, Mori T, Takahashi K. Elevated (Pro)renin Receptor Expression by Anti-Cancer Drugs, Carboplatin and Paclitaxel, in Cultured Cancer Cells: Possible Involvement of Apoptosis and Autophagy. TOHOKU J EXP MED 2021; 255:91-104. [PMID: 34645770 DOI: 10.1620/tjem.255.91] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
(Pro)renin receptor [(P)RR] is a component of the renin-angiotensin system and plays an essential role in the activity of vacuolar H+-ATPase and autophagy. (P)RR is expressed in cancer cells. However, the relationship among (P)RR, apoptosis and autophagy in the treatment of anti-cancer drugs has not been clarified. The aim of this study was to clarify the effects of anti-cancer drugs with autophagy-promoting activity on (P)RR expression in cancer cells. MCF-7 breast cancer cells and A549 lung cancer cells were treated with carboplatin or paclitaxel, and the expression of (P)RR, apoptosis markers and autophagy markers were assessed by RT-qPCR, western blot analysis and immunocytochemistry. Expression levels of (P)RR mRNA and soluble (P)RR protein were increased by carboplatin or paclitaxel in a dose-dependent manner. Immunofluorescence staining of (P)RR was increased in both MCF-7 and A549 cells treated by carboplatin or paclitaxel. Apoptosis induction was shown by elevated BAX/BCL2 mRNA levels and increased active caspase3-positive cells. Moreover, autophagy induction was confirmed by increased levels of autophagy-associated mRNAs and LC3B-II proteins. (P)RR knockdown by (P)RR-specific siRNA suppressed the cell viability in MCF-7 cells and A549 cells under the treatment of carboplatin or paclitaxel, suggesting that (P)RR deficiency inhibits the proliferation of cancer cells in a pathway different from carboplatin or paclitaxel. The present study showed that the expression of (P)RR mRNA and soluble (P)RR was increased by anti-cancer drugs with autophagy-promoting activity. Upregulated (P)RR and autophagy may constitute a stress adaptation that protects cancer cells from apoptosis.
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Affiliation(s)
- Yurina Kashio-Yokota
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Shigemitsu Sato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Takuo Hirose
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine.,Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University.,Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University
| | - Tomoki Watanabe
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Akari Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine.,Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University
| | - Fumihiko Watanabe
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Moe Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Koji Ohba
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University.,Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine
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20
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Banu K, Lin Q, Basgen JM, Planoutene M, Wei C, Reghuvaran AC, Tian X, Shi H, Garzon F, Garzia A, Chun N, Cumpelik A, Santeusanio AD, Zhang W, Das B, Salem F, Li L, Ishibe S, Cantley LG, Kaufman L, Lemley KV, Ni Z, He JC, Murphy B, Menon MC. AMPK mediates regulation of glomerular volume and podocyte survival. JCI Insight 2021; 6:e150004. [PMID: 34473647 PMCID: PMC8525649 DOI: 10.1172/jci.insight.150004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/01/2021] [Indexed: 12/20/2022] Open
Abstract
Herein, we report that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without focal segmental glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease (MCD), where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral and 5/6th nephrectomy models in Shroom3-KD mice. Knockdown mice exhibited less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying that Fyn was downstream of Shroom3. Using SHROOM3 or FYN knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMPK, a negative regulator of anabolism. AMPK activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMPK abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMPK activation. In agreement with this, treatment of glomerular injury models with AMPK activators restricted glomerular volume, podocytopenia, and progression to FSGS. Glomerular transcriptomes from MCD biopsies also showed significant enrichment of Fyn inactivation and Ampk activation versus FSGS glomeruli. In summary, we demonstrated the important role of AMPK in glomerular volume regulation and podocyte survival. Our data suggest that AMPK activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.
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Affiliation(s)
- Khadija Banu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Qisheng Lin
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - John M Basgen
- Morphometry and Stereology Laboratory, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
| | - Marina Planoutene
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chengguo Wei
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Anand C Reghuvaran
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Xuefei Tian
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Hongmei Shi
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Felipe Garzon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aitor Garzia
- Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York, USA
| | - Nicholas Chun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Arun Cumpelik
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Andrew D Santeusanio
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Bhaskar Das
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Fadi Salem
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Li Li
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Shuta Ishibe
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lloyd G Cantley
- Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lewis Kaufman
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Kevin V Lemley
- Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Barbara Murphy
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Madhav C Menon
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Division of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
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21
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Hoffmann N, Peters J. Functions of the (pro)renin receptor (Atp6ap2) at molecular and system levels: pathological implications in hypertension, renal and brain development, inflammation, and fibrosis. Pharmacol Res 2021; 173:105922. [PMID: 34607004 DOI: 10.1016/j.phrs.2021.105922] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/16/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
The (pro)renin receptor [(P)RR, Atp6ap2] was initially discovered as a membrane-bound binding partner of prorenin and renin. A soluble (P)RR has additional paracrine effects and is involved in metabolic syndrome and kidney damage. Meanwhile it is clear that most of the effects of the (P)RR are independent of prorenin. In the kidney, (P)RR plays an important role in renal dysfunction by activating proinflammatory and profibrotic molecules. In the brain, (P)RR is expressed in cardiovascular regulatory nuclei and is linked to hypertension. (P)RR is known to be an essential component of the v-ATPase as a key accessory protein and plays an important role in kidney, brain and heart via regulating the pH of the extracellular space and intracellular compartments. V-ATPase and (P)RR together act on WNT and mTOR signalling pathways, which are responsible for cellular homeostasis and autophagy. (P)RR through its role in v-ATPase assembly and function is also important for fast recycling endocytosis by megalin. In the kidney, megalin together with v-ATPase and (P)RR is crucial for endocytic uptake of components of the RAS and their intracellular processing. In the brain, (P)RR, v-ATPases and megalin are important regulators both during development and in the adult. All three proteins are associated with diseases such as XLMR, XMRE, X-linked parkinsonism and epilepsy, cognitive disorders with Parkinsonism, spasticity, intellectual disability, and Alzheimer's Disease which are characterized by impaired neuronal function and/or neuronal loss. The present review focusses on the relevant effects of Atp6ap2 without assigning them necessarily to the RAS. Mechanistically, many effects can be well explained by the role of Atp6ap2 for v-ATPase assembly and function. Furthermore, application of a soluble (P)RR analogue as new therapeutic option is discussed.
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Affiliation(s)
- Nadin Hoffmann
- Institute of Physiology, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, 17475, Greifswald, Germany
| | - Jörg Peters
- Institute of Physiology, University Medicine Greifswald, Friedrich-Ludwig-Jahn-Str. 15A, 17475, Greifswald, Germany.
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22
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Qin M, Xu C, Yu J. The Soluble (Pro)Renin Receptor in Health and Diseases: Foe or Friend? J Pharmacol Exp Ther 2021; 378:251-261. [PMID: 34158404 DOI: 10.1124/jpet.121.000576] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022] Open
Abstract
The (pro)renin receptor (PRR) is a single-transmembrane protein that regulates the local renin-angiotensin system and participates in various intracellular signaling pathways, thus exhibiting a significant physiopathologic relevance in cellular homeostasis. A soluble form of PRR (sPRR) is generated through protease-mediated cleavage of the full-length PRR and secreted into extracellular spaces. Accumulating evidence indicates pivotal biologic functions of sPRR in various physiopathological processes. sPRR may be a novel biomarker for multiple diseases. SIGNIFICANCE STATEMENT: Circulating sPRR concentrations are elevated in patients and animals under various physiopathological conditions. This minireview highlights recent advances in sPRR functions in health and pathophysiological conditions. Results suggest that sPRR may be a novel biomarker for multiple diseases, but further studies are needed to determine the diagnostic value of sPRR.
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Affiliation(s)
- Manman Qin
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China (M.Q., C.X.), and Center for Metabolic Disease Research and Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania (J.Y.)
| | - Chuanming Xu
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China (M.Q., C.X.), and Center for Metabolic Disease Research and Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania (J.Y.)
| | - Jun Yu
- Translational Medicine Centre, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China (M.Q., C.X.), and Center for Metabolic Disease Research and Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania (J.Y.)
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23
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Yildirim D, Bender O, Karagoz ZF, Helvacioglu F, Bilgic MA, Akcay A, Ruzgaresen NB. Role of autophagy and evaluation the effects of microRNAs 214, 132, 34c and prorenin receptor in a rat model of focal segmental glomerulosclerosis. Life Sci 2021; 280:119671. [PMID: 34087284 DOI: 10.1016/j.lfs.2021.119671] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/13/2021] [Accepted: 05/26/2021] [Indexed: 12/24/2022]
Abstract
AIMS Focal segmental glomerulosclerosis (FSGS) is the common cause of chronic renal disease worldwide. Although there are many etiologic factors which have common theme of podocyte injury conclusive etiology is not clearly understood. In this study, we aimed to explore the role of autophagy in the pathogenesis of podocyte injury, which is the key point in disease progression, and the roles of intrarenal microRNAs and the prorenin receptor (PRR) in the 5/6 nephrectomy and adriamycin nephropathy models of FSGS. MAIN METHODS For experimental FSGS model, 5/6 nephrectomy and adriamycin nephropathy models were created and characterized in adult Sprague Dawley rats. Microarray analysis was performed on FSGS and control groups that was confirmed by q-RT-PCR. Beclin1, LC3B, PRR, ATG7 and ATG5 expression were evaluated by western blotting and immunohistochemistry. Also, Beclin1 and PRR expression were measured by ELISA. Glomerular podocyte isolation was performed and autophagic activity was evaluated in podocytes before and after transfection with miRNA mimic and antagonists. KEY FINDINGS Glomerular expression of Beclin1, LC3B, PRR, ATG7 and ATG5 were significantly lower in the 5/6 nephrectomy than adriamycin nephropathy group and in both groups lower when compared to control groups. Western blot results were consistent with immunohistochemical data. Electron microscopy revealed signs of impaired autophagy in FSGS. Autophagic activity decreased significantly after miR-214, miR-132 and miR-34c mimics and increased after transfection with antagonists. SIGNIFICANCE These results showed that the role of autophagic activity and decreased expression of PRR in FSGS pathogenesis and miR-34c, miR-132 and miR-214 could be a potential treatment strategy by regulating autophagy.
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Affiliation(s)
- Derya Yildirim
- Department of Internal Medicine, Ankara Education and Research Hospital, Ankara, Turkey.
| | - Onur Bender
- Biotechnology Institute, Ankara University, Ankara, Turkey
| | - Zehra Firat Karagoz
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Fatma Helvacioglu
- Department of Histology and Embryology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | | | - Ali Akcay
- Department of Nephrology, Koru Hospital, Ankara, Turkey
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24
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NADPH-Oxidase, Rho-Kinase and Autophagy Mediate the (Pro)renin-Induced Pro-Inflammatory Microglial Response and Enhancement of Dopaminergic Neuron Death. Antioxidants (Basel) 2021; 10:antiox10091340. [PMID: 34572972 PMCID: PMC8472832 DOI: 10.3390/antiox10091340] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/12/2021] [Accepted: 08/20/2021] [Indexed: 11/16/2022] Open
Abstract
Dysregulation of the tissue renin–angiotensin system (RAS) is involved in tissue oxidative and inflammatory responses. Among RAS components, renin, its precursor (pro)renin and its specific receptor (PRR) have been less investigated, particularly in the brain. We previously showed the presence of PRR in neurons and glial cells in the nigrostriatal system of rodents and primates, including humans. Now, we used rat and mouse models and cultures of BV2 and primary microglial cells to study the role of PRR in microglial pro-inflammatory responses. PRR was upregulated in the nigral region, particularly in microglia during the neuroinflammatory response. In the presence of the angiotensin type-1 receptor blocker losartan, to exclude angiotensin-related effects, treatment of microglial cells with (pro)renin induces the expression of microglial pro-inflammatory markers, which is mediated by upregulation of NADPH-oxidase and Rho-kinase activities, downregulation of autophagy and upregulation of inflammasome activity. Conditioned medium from (pro)renin-treated microglia increased dopaminergic cell death relative to medium from non-treated microglia. However, these effects were blocked by pre-treatment of microglia with the Rho-kinase inhibitor fasudil. Activation of microglial PRR enhances the microglial pro-inflammatory response and deleterious effects of microglia on dopaminergic cells, and microglial NADPH-oxidase, Rho-Kinase and autophagy are involved in this process.
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25
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Figueiredo M, Daryadel A, Sihn G, Müller DN, Popova E, Rouselle A, Nguyen G, Bader M, Wagner CA. The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule. Pflugers Arch 2021; 473:1229-1246. [PMID: 34228176 PMCID: PMC8302575 DOI: 10.1007/s00424-021-02598-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/26/2021] [Accepted: 06/16/2021] [Indexed: 12/16/2022]
Abstract
The ATP6ap2 (Pro)renin receptor protein associates with H+-ATPases which regulate organellar, cellular, and systemic acid-base homeostasis. In the kidney, ATP6ap2 colocalizes with H+-ATPases in various cell types including the cells of the proximal tubule. There, H+-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H+-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H+-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats.
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Affiliation(s)
- Marta Figueiredo
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Arezoo Daryadel
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland
| | - Gabin Sihn
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Dominik N Müller
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
- Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Elena Popova
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | - Anthony Rouselle
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany
| | | | - Michael Bader
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Str. 10, 13125, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
- Charite University Medicine Berlin, Berlin, Germany.
- Institute for Biology, University of Lübeck, Lübeck, Germany.
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
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26
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Peters J. "Nomen not est omen": the (pro)renin receptor and receptor-mediated endocytosis in the proximal tubule-a new (pro)renin-independent role forATP6ap2. Pflugers Arch 2021; 473:1173-1174. [PMID: 34240240 PMCID: PMC8302501 DOI: 10.1007/s00424-021-02597-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 11/24/2022]
Affiliation(s)
- Jörg Peters
- Institute of Physiology, University Medicine of Greifswald, Friedrich-Ludwig-Jahn-Str. 15a, 17475, Greifswald, Germany.
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27
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Ramkumar N, Stuart D, Peterson CS, Hu C, Wheatley W, Cho JM, Symons JD, Kohan DE. Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury. Circ Res 2021; 129:50-62. [PMID: 33890822 PMCID: PMC8225587 DOI: 10.1161/circresaha.120.317532] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Nirupama Ramkumar
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Deborah Stuart
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Caitlin S. Peterson
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Chunyan Hu
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - William Wheatley
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
| | - Jae Min Cho
- Nutrition and Integrative Physiology, University of Utah Health,Salt Lake City, UT
| | - J David Symons
- Nutrition and Integrative Physiology, University of Utah Health,Salt Lake City, UT
- Endocrinology, Metabolism and Diabetes, and Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT
| | - Donald E Kohan
- Division of Nephrology and Hypertension, University of Utah Health, Salt Lake City, UT
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28
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Wang YL, Lee YH, Hsu YH, Chiu IJ, Huang CCY, Huang CC, Chia ZC, Lee CP, Lin YF, Chiu HW. The Kidney-Related Effects of Polystyrene Microplastics on Human Kidney Proximal Tubular Epithelial Cells HK-2 and Male C57BL/6 Mice. ENVIRONMENTAL HEALTH PERSPECTIVES 2021; 129:57003. [PMID: 33956507 PMCID: PMC8101928 DOI: 10.1289/ehp7612] [Citation(s) in RCA: 179] [Impact Index Per Article: 44.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 03/19/2021] [Accepted: 04/12/2021] [Indexed: 05/19/2023]
Abstract
BACKGROUND Understanding the epidemic of chronic kidney disease of uncertain etiology may be critical for health policies and public health responses. Recent studies have shown that microplastics (MPs) contaminate our food chain and accumulate in the gut, liver, kidney, muscle, and so on. Humans manufacture many plastics-related products. Previous studies have indicated that particles of these products have several effects on the gut and liver. Polystyrene (PS)-MPs (PS-MPs) induce several responses, such as oxidative stress, and affect living organisms. OBJECTIVES The aim of this study was to investigate the effects of PS-MPs in kidney cells in vitro and in vivo. METHODS PS-MPs were evaluated in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6 mice. Mitochondrial reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, inflammation, and autophagy were analyzed in kidney cells. In vivo, we evaluated biomarkers of kidney function, kidney ultrastructure, muscle mass, and grip strength, and urine protein levels, as well as the accumulation of PS-MPs in the kidney tissue. RESULTS Uptake of PS-MPs at different concentrations by HK-2 cells resulted in higher levels of mitochondrial ROS and the mitochondrial protein Bad. Cells exposed to PS-MPs had higher ER stress and markers of inflammation. MitoTEMPO, which is a mitochondrial ROS antioxidant, mitigated the higher levels of mitochondrial ROS, Bad, ER stress, and specific autophagy-related proteins seen with PS-MP exposure. Furthermore, cells exposed to PS-MPs had higher protein levels of LC3 and Beclin 1. PS-MPs also had changes in phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT)/mitogen-activated protein kinase (mTOR) signaling pathways. In an in vivo study, PS-MPs accumulated and the treated mice had more histopathological lesions in the kidneys and higher levels of ER stress, inflammatory markers, and autophagy-related proteins in the kidneys after PS-MPs treatment by oral gavage. CONCLUSIONS The results suggest that PS-MPs caused mitochondrial dysfunction, ER stress, inflammation, and autophagy in kidney cells and accumulated in HK-2 cells and in the kidneys of mice. These results suggest that long-term PS-MPs exposure may be a risk factor for kidney health. https://doi.org/10.1289/EHP7612.
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Affiliation(s)
- Yung-Li Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Hsuan Lee
- Department of Cosmeceutics, China Medical University, Taichung, Taiwan
| | - Yung-Ho Hsu
- Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
| | - I-Jen Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
| | - Cathy Chia-Yu Huang
- Department of Life Sciences, National Central University, Taoyuan City, Taiwan
| | - Chih-Chia Huang
- Department of Photonics, Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Zi-Chun Chia
- Department of Photonics, Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Pei Lee
- School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Yuh-Feng Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Internal Medicine, School of Medicine, National Defense Medical Center, Taipei, Taiwan
| | - Hui-Wen Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
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Racetin A, Filipović N, Lozić M, Ogata M, Gudelj Ensor L, Kelam N, Kovačević P, Watanabe K, Katsuyama Y, Saraga-Babić M, Glavina Durdov M, Vukojević K. A Homozygous Dab1 -/- Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract. Biomolecules 2021; 11:biom11040609. [PMID: 33924028 PMCID: PMC8073787 DOI: 10.3390/biom11040609] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 01/09/2023] Open
Abstract
This study aimed to explore morphology changes in the kidneys of Dab1−/− (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari.
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Affiliation(s)
- Anita Racetin
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
- Department of Medical Genetics, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina;
| | - Natalija Filipović
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
| | - Mirela Lozić
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
| | - Masaki Ogata
- Division of Anatomy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi 981-8558, Japan;
| | - Larissa Gudelj Ensor
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
| | - Nela Kelam
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
| | - Petra Kovačević
- Department of Medical Genetics, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina;
| | - Koichiro Watanabe
- Department of Anatomy, Shiga University of Medical Science, Ötsu 520-2192, Japan; (K.W.); (Y.K.)
| | - Yu Katsuyama
- Department of Anatomy, Shiga University of Medical Science, Ötsu 520-2192, Japan; (K.W.); (Y.K.)
| | - Mirna Saraga-Babić
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
| | | | - Katarina Vukojević
- Department of Anatomy, Histology and Embryology, University of Split School of Medicine, 21000 Split, Croatia; (A.R.); (N.F.); (M.L.); (L.G.E.); (N.K.); (M.S.-B.)
- Department of Medical Genetics, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina;
- Correspondence: ; Tel.: +385-21-557-807; Fax: +385-1-557-811
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Quadri SS, Cooper C, Ghaffar D, Vaishnav H, Nahar L. The Pathological Role of Pro(Renin) Receptor in Renal Inflammation. J Exp Pharmacol 2021; 13:339-344. [PMID: 33776491 PMCID: PMC7989955 DOI: 10.2147/jep.s297682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 02/23/2021] [Indexed: 12/17/2022] Open
Abstract
(Pro)renin receptor (PRR) is the recently discovered component of the renin-angiotensin-aldosterone system (RAS). Many organs contain their own RAS, wherein PRR can exert organ-specific localized effects. The Binding of prorenin/renin to PRR activates angiotensin-dependent and independent pathways which leads to the development of physiological and pathological effects. Continued progress in PRR research suggests that the upregulation of PRR contributes to the development of hypertension, glomerular injury, and progression of kidney disease and inflammation. In the current review, we highlight the function of the PRR in renal inflammation in pathophysiological conditions.
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Affiliation(s)
- Syed S Quadri
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Caleb Cooper
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN, USA
| | - Dawood Ghaffar
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Hitesh Vaishnav
- DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Knoxville, TN, USA
| | - Ludmila Nahar
- Department of Medicine, School of Medicine/John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, USA
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31
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Lin Q, Banu K, Ni Z, Leventhal JS, Menon MC. Podocyte Autophagy in Homeostasis and Disease. J Clin Med 2021; 10:jcm10061184. [PMID: 33809036 PMCID: PMC7998595 DOI: 10.3390/jcm10061184] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Autophagy is a protective mechanism that removes dysfunctional components and provides nutrition for cells. Podocytes are terminally differentiated specialized epithelial cells that wrap around the capillaries of the glomerular filtration barrier and show high autophagy level at the baseline. Here, we provide an overview of cellular autophagy and its regulation in homeostasis with specific reference to podocytes. We discuss recent data that have focused on the functional role and regulation of autophagy during podocyte injury in experimental and clinical glomerular diseases. A thorough understanding of podocyte autophagy could shed novel insights into podocyte survival mechanisms with injury and offer potential targets for novel therapeutics for glomerular disease.
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Affiliation(s)
- Qisheng Lin
- Division of Nephrology, Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (Q.L.); (K.B.); (J.S.L.)
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Khadija Banu
- Division of Nephrology, Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (Q.L.); (K.B.); (J.S.L.)
- Division of Nephrology, Yale School of Medicine, New Haven, CT 06510, USA
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China;
| | - Jeremy S. Leventhal
- Division of Nephrology, Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (Q.L.); (K.B.); (J.S.L.)
| | - Madhav C. Menon
- Division of Nephrology, Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (Q.L.); (K.B.); (J.S.L.)
- Division of Nephrology, Yale School of Medicine, New Haven, CT 06510, USA
- Correspondence:
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32
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Renin-angiotensin system in mammalian kidney development. Pediatr Nephrol 2021; 36:479-489. [PMID: 32072306 DOI: 10.1007/s00467-020-04496-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/30/2020] [Accepted: 01/31/2020] [Indexed: 12/20/2022]
Abstract
Mutations in the genes of the renin-angiotensin system result in congenital anomalies of the kidney and urinary tract (CAKUT), the main cause of end-stage renal disease in children. The molecular mechanisms that cause CAKUT are unclear in most cases. To improve the care of children with CAKUT, it is critical to determine the underlying mechanisms of CAKUT. In this review, we discuss recent advances that have helped to better understand how disruption of the renin-angiotensin system during kidney development contributes to CAKUT.
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Gatineau E, Arthur G, Poupeau A, Nichols K, Spear BT, Shelman NR, Graf GA, Temel RE, Yiannikouris FB. The prorenin receptor and its soluble form contribute to lipid homeostasis. Am J Physiol Endocrinol Metab 2021; 320:E609-E618. [PMID: 33459178 PMCID: PMC7988779 DOI: 10.1152/ajpendo.00135.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARγ) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk.NEW & NOTEWORTHY Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARγ-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.
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Affiliation(s)
- Eva Gatineau
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Gertrude Arthur
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Audrey Poupeau
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Kellea Nichols
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Brett T Spear
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky
| | - Nathan R Shelman
- Department of Pathology & Laboratory Medicine, University of Kentucky, Lexington, Kentucky
| | - Gregory A Graf
- Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky
| | - Ryan E Temel
- Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Kentucky
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34
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Hsu CN, Tain YL. Targeting the Renin-Angiotensin-Aldosterone System to Prevent Hypertension and Kidney Disease of Developmental Origins. Int J Mol Sci 2021; 22:ijms22052298. [PMID: 33669059 PMCID: PMC7956566 DOI: 10.3390/ijms22052298] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
The renin-angiotensin-aldosterone system (RAAS) is implicated in hypertension and kidney disease. The developing kidney can be programmed by various early-life insults by so-called renal programming, resulting in hypertension and kidney disease in adulthood. This theory is known as developmental origins of health and disease (DOHaD). Conversely, early RAAS-based interventions could reverse program processes to prevent a disease from occurring by so-called reprogramming. In the current review, we mainly summarize (1) the current knowledge on the RAAS implicated in renal programming; (2) current evidence supporting the connections between the aberrant RAAS and other mechanisms behind renal programming, such as oxidative stress, nitric oxide deficiency, epigenetic regulation, and gut microbiota dysbiosis; and (3) an overview of how RAAS-based reprogramming interventions may prevent hypertension and kidney disease of developmental origins. To accelerate the transition of RAAS-based interventions for prevention of hypertension and kidney disease, an extended comprehension of the RAAS implicated in renal programming is needed, as well as a greater focus on further clinical translation.
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Affiliation(s)
- Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: ; Tel.: +886-975-056-995; Fax: +886-7733-8009
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35
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Arthur G, Osborn JL, Yiannikouris FB. (Pro)renin receptor in the kidney: function and significance. Am J Physiol Regul Integr Comp Physiol 2021; 320:R377-R383. [PMID: 33470188 DOI: 10.1152/ajpregu.00259.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.
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Affiliation(s)
- Gertrude Arthur
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky
| | - Jeffrey L Osborn
- Department of Biology, University of Kentucky, Lexington, Kentucky
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36
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Bgatova N, Taskaeva I. Ultrastructure of the kidney filtration barrier in conditions of distant tumor growth and lithium treatment. Ultrastruct Pathol 2020; 44:412-421. [DOI: 10.1080/01913123.2020.1850962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Nataliya Bgatova
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Iuliia Taskaeva
- Laboratory of Ultrastructural Research, Research Institute of Clinical and Experimental Lymphology – Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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37
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Ohba K, Endo M, Sato S, Kashio-Yokota Y, Hirose T, Takahashi K. (Pro)renin receptor/ATP6AP2 is required for autophagy and regulates proliferation in lung adenocarcinoma cells. Genes Cells 2020; 25:782-795. [PMID: 33020972 DOI: 10.1111/gtc.12812] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 09/16/2020] [Accepted: 09/26/2020] [Indexed: 12/26/2022]
Abstract
(Pro)renin receptor ((P)RR)/ ATP6AP2 (ATPase, H+ transporting, lysosomal accessory protein 2) functions as an essential accessory subunit of vacuolar H+ -ATPase (V-ATPase). V-ATPase is necessary for lysosome function and autophagy. Autophagy is related to cell proliferation, migration and invasion of various cancer cells. In this study, we aim to clarify the relationship between (P)RR and autophagy in lung adenocarcinoma. Expression of (P)RR and Ki-67 (a proliferation marker) was studied in sixty-four adenocarcinoma cases by immunohistochemistry. Lung adenocarcinoma cell line, A549, was transfected with (P)RR-specific siRNA. Autophagy inhibitors, bafilomycin A1 and chloroquine, were used as positive controls. Cell proliferation and migration were measured by WST-8 assay and wound healing assay. Autophagosome markers, p62 and LC3, were analyzed by RT-qPCR, Western blot and immunocytochemistry. Immunohistochemistry showed that (P)RR was expressed in all adenocarcinoma tissues. The intensity of (P)RR immunoreactivity was significantly associated with Ki-67. Treatment of (P)RR-specific siRNA suppressed (P)RR expression and significantly reduced cell proliferation and migration as did the autophagy inhibitors. Western blot and immunocytochemistry showed that (P)RR-specific siRNA, as well as the autophagy inhibitors, induced p62 and LC3 accumulation in cytoplasmic granules. These results suggest that (P)RR is involved in cell proliferation and progression of lung adenocarcinoma via regulating autophagy.
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Affiliation(s)
- Koji Ohba
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Moe Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigemitsu Sato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yurina Kashio-Yokota
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuo Hirose
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
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WNT-β-catenin signalling - a versatile player in kidney injury and repair. Nat Rev Nephrol 2020; 17:172-184. [PMID: 32989282 DOI: 10.1038/s41581-020-00343-w] [Citation(s) in RCA: 268] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2020] [Indexed: 12/11/2022]
Abstract
The WNT-β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT-β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT-β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT-β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT-β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by 'stressed' tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT-β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.
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39
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Chen Y, Xu C. The interaction partners of (pro)renin receptor in the distal nephron. FASEB J 2020; 34:14136-14149. [PMID: 32975331 DOI: 10.1096/fj.202001711r] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/10/2020] [Accepted: 09/11/2020] [Indexed: 11/11/2022]
Abstract
The (pro)renin receptor (PRR), a key regulator of intrarenal renin-angiotensin system (RAS), is predominantly presented in podocytes, proximal tubules, distal convoluted tubules, and the apical membrane of collecting duct A-type intercalated cells, and plays a crucial role in hypertension, cardiovascular disease, kidney disease, and fluid homeostasis. In addition to its well-known renin-regulatory function, increasing evidence suggests PRR can also act in a variety of intracellular signaling cascades independently of RAS in the renal medulla, including Wnt/β-catenin signaling, cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2 ) signaling, and the apelinergic system, and work as a component of the vacuolar H+ -ATPase. PRR and these pathways regulate the expression/activity of each other that controlling blood pressure and renal functions. In this review, we highlight recent findings regarding the antagonistic interaction between PRR and ELABELA/apelin, the mutually stimulatory relationship between PRR and COX-2/PGE2 or Wnt/β-catenin signaling in the renal medulla, and their involvement in the regulation of intrarenal RAS thereby control blood pressure, renal injury, and urine concentrating ability in health and patho-physiological conditions. We also highlight the latest progress in the involvement of PRR for the vacuolar H+ -ATPase activity.
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Affiliation(s)
- Yanting Chen
- Institute of Hypertension, Sun Yat-sen University School of Medicine, Guangzhou, China.,Internal Medicine, Division of Nephrology and Hypertension, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, USA
| | - Chuanming Xu
- Internal Medicine, Division of Nephrology and Hypertension, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT, USA.,Center for Translational Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
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40
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Role of the renin-angiotensin system in kidney development and programming of adult blood pressure. Clin Sci (Lond) 2020; 134:641-656. [PMID: 32219345 DOI: 10.1042/cs20190765] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 03/10/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023]
Abstract
Adverse events during fetal life such as insufficient protein intake or elevated transfer of glucocorticoid to the fetus may impact cardiovascular and metabolic health later in adult life and are associated with increased incidence of type 2 diabetes, ischemic heart disease and hypertension. Several adverse factors converge and suppress the fetal renin-angiotensin-aldosterone system (RAAS). The aim of this review is to summarize data on the significance of RAAS for kidney development and adult hypertension. Genetic inactivation of RAAS in rodents at any step from angiotensinogen to angiotensin II (ANGII) type 1 receptor (AT1) receptors or pharmacologic inhibition leads to complex developmental injury to the kidneys that has also been observed in human case reports. Deletion of the 'protective' arm of RAAS, angiotensin converting enzyme (ACE) 2 (ACE-2) and G-protein coupled receptor for Angiotensin 1-7 (Mas) receptor does not reproduce the AT1 phenotype. The changes comprise fewer glomeruli, thinner cortex, dilated tubules, thicker arterioles and arteries, lack of vascular bundles, papillary atrophy, shorter capillary length and volume in cortex and medulla. Altered activity of systemic and local regulators of fetal-perinatal RAAS such as vitamin D and cyclooxygenase (COX)/prostaglandins are associated with similar injuries. ANGII-AT1 interaction drives podocyte and epithelial cell formation of vascular growth factors, notably vascular endothelial growth factor (VEGF) and angiopoietins (Angpts), which support late stages of glomerular and cortical capillary growth and medullary vascular bundle formation and patterning. RAAS-induced injury is associated with lower glomerular filtration rate (GFR), lower renal plasma flow, kidney fibrosis, up-regulation of sodium transporters, impaired sodium excretion and salt-sensitive hypertension. The renal component and salt sensitivity of programmed hypertension may impact dietary counseling and choice of pharmacological intervention to treat hypertension.
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41
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Endo M, Ohba K, Sato S, Yokota Y, Takahashi K. Increased soluble (pro)renin receptor protein by autophagy inhibition in cultured cancer cells. Genes Cells 2020; 25:483-497. [PMID: 32314441 DOI: 10.1111/gtc.12776] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/17/2020] [Accepted: 04/15/2020] [Indexed: 12/18/2022]
Abstract
(Pro)renin receptor ((P)RR) regulates the renin-angiotensin system and functions as an essential accessory subunit of vacuolar H+ -ATPase. There is accumulating evidence that shows close relationship between (P)RR and autophagy. Soluble (P)RR consisting of the extracellular domain of (P)RR is generated from (P)RR by proteolytic enzymes. The aim of the present study was to clarify the influence of autophagy inhibition on soluble (P)RR expression in cancer cells. Autophagy was inhibited by treatment of bafilomycin A1 or chloroquine in MCF-7 and A549 cells for 72 hr. Western blot analysis showed that protein levels of soluble (P)RR were markedly elevated by autophagy inhibition, whereas no noticeable increases were observed in full-length (P)RR. Secretion of soluble (P)RR into the medium was increased dose-dependently by bafilomycin A1 or chloroquine. Autophagy inhibition was confirmed by enhanced accumulation of autophagy-related proteins, LC3, p62 and LAMP1 in intracellular vesicles. Increased amount of soluble (P)RR by autophagy inhibition was decreased by site-1 protease inhibitor, whereas no noticeable increase in site-1 protease immunoreactivity was observed in cells with autophagy inhibition by immunocytochemistry. These findings suggest that soluble (P)RR protein accumulates by autophagy inhibition, possibly because of the reduced degradation of soluble (P)RR in the intracellular vesicles during autophagy inhibition.
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Affiliation(s)
- Moe Endo
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koji Ohba
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigemitsu Sato
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yurina Yokota
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuhiro Takahashi
- Department of Endocrinology and Applied Medical Science, Tohoku University Graduate School of Medicine, Sendai, Japan
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Gao X, Zhang S, Wang D, Cheng Y, Jiang Y, Liu Y. (Pro)renin receptor contributes to hypoxia/reoxygenation-induced apoptosis and autophagy in myocardial cells via the beta-catenin signaling pathway. Physiol Res 2020; 69:427-438. [PMID: 32469229 DOI: 10.33549/physiolres.934210] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
(Pro)renin receptor (PRR) contributes to regulating many physiological and pathological processes; however, the role of PRR-mediated signaling pathways in myocardial ischemia/reperfusion injury (IRI) remains unclear. In this study, we used an in vitro model of hypoxia/reoxygenation (H/R) to mimic IRI and carried out PRR knockdown by siRNA and PRR overexpression using cDNA in H9c2 cells. Cell proliferation activity was examined by MTT and Cell Counting Kit-8 (CCK-8) assays. Apoptosis-related factors, autophagy markers and beta-catenin pathway activity were assessed by real-time PCR and western blotting. After 24 h of hypoxia followed by 2 h of reoxygenation, the expression levels of PRR, LC3B-I/II, Beclin1, cleaved caspase-3, cleaved caspase-9 and Bax were upregulated, suggesting that apoptosis and autophagy were increased in H9c2 cells. Contrary to the effects of PRR downregulation, the overexpression of PRR inhibited proliferation, induced apoptosis, increased the expression of pro-apoptotic factors and autophagy markers, and promoted activation of the beta-catenin pathway. Furthermore, all these effects were reversed by treatment with the beta-catenin antagonist DKK-1. Thus, we concluded that PRR activation can trigger H/R-induced apoptosis and autophagy in H9c2 cells through the beta-catenin signaling pathway, which may provide new therapeutic targets for the prevention and treatment of myocardial IRI.
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Affiliation(s)
- X Gao
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People's Republic of China.
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Abstract
The (pro)renin receptor ((P)RR) was first identified as a single-transmembrane receptor in human kidneys and initially attracted attention owing to its potential role as a regulator of the tissue renin-angiotensin system (RAS). Subsequent studies found that the (P)RR is widely distributed in organs throughout the body, including the kidneys, heart, brain, eyes, placenta and the immune system, and has multifaceted functions in vivo. The (P)RR has roles in various physiological processes, such as the cell cycle, autophagy, acid-base balance, energy metabolism, embryonic development, T cell homeostasis, water balance, blood pressure regulation, cardiac remodelling and maintenance of podocyte structure. These roles of the (P)RR are mediated by its effects on important biological systems and pathways including the tissue RAS, vacuolar H+-ATPase, Wnt, partitioning defective homologue (Par) and tyrosine phosphorylation. In addition, the (P)RR has been reported to contribute to the pathogenesis of diseases such as fibrosis, hypertension, pre-eclampsia, diabetic microangiopathy, acute kidney injury, cardiovascular disease, cancer and obesity. Current evidence suggests that the (P)RR has key roles in the normal development and maintenance of vital organs and that dysfunction of the (P)RR is associated with diseases that are characterized by a disruption of the homeostasis of physiological functions.
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Bhatia D, Choi ME. Autophagy in kidney disease: Advances and therapeutic potential. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 172:107-133. [PMID: 32620239 DOI: 10.1016/bs.pmbts.2020.01.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Autophagy is a highly conserved intracellular catabolic process for the degradation of cytoplasmic components that has recently gained increasing attention for its importance in kidney diseases. It is indispensable for the maintenance of kidney homeostasis both in physiological and pathological conditions. Investigations utilizing various kidney cell-specific conditional autophagy-related gene knockouts have facilitated the advancement in understanding of the role of autophagy in the kidney. Recent findings are raising the possibility that defective autophagy exerts a critical role in different pathological conditions of the kidney. An emerging body of evidence reveals that autophagy exhibits cytoprotective functions in both glomerular and tubular compartments of the kidney, suggesting the upregulation of autophagy as an attractive therapeutic strategy. However, there is also accumulating evidence that autophagy could be deleterious, which presents a formidable challenge in developing therapeutic strategies targeting autophagy. Here, we review the recent advances in research on the role of autophagy during different pathological conditions, including acute kidney injury (AKI), focusing on sepsis, ischemia-reperfusion injury, cisplatin, and heavy metal-induced AKI. We also discuss the role of autophagy in chronic kidney disease (CKD) focusing on the pathogenesis of tubulointerstitial fibrosis, podocytopathies including focal segmental glomerulosclerosis, diabetic nephropathy, IgA nephropathy, membranous nephropathy, HIV-associated nephropathy, and polycystic kidney disease.
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Affiliation(s)
- Divya Bhatia
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United States
| | - Mary E Choi
- Division of Nephrology and Hypertension, Joan and Sanford I. Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United States.
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Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome. PLoS One 2020; 15:e0228337. [PMID: 31978139 PMCID: PMC6980606 DOI: 10.1371/journal.pone.0228337] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022] Open
Abstract
Autophagy is a cellular mechanism involved in the bulk degradation of proteins and turnover of organelle. Several studies have shown the significance of autophagy of the renal tubular epithelium in rodent models of tubulointerstitial disorder. However, the role of autophagy in the regulation of human glomerular diseases is largely unknown. The current study aimed to demonstrate morphological evidence of autophagy and its association with the ultrastructural changes of podocytes and clinical data in patients with idiopathic nephrotic syndrome, a disease in which patients exhibit podocyte injury. The study population included 95 patients, including patients with glomerular disease (minimal change nephrotic syndrome [MCNS], n = 41; idiopathic membranous nephropathy [IMN], n = 37) and 17 control subjects who underwent percutaneous renal biopsy. The number of autophagic vacuoles and the grade of foot process effacement (FPE) in podocytes were examined by electron microscopy (EM). The relationships among the expression of autophagic vacuoles, the grade of FPE, and the clinical data were determined. Autophagic vacuoles were mainly detected in podocytes by EM. The microtubule-associated protein 1 light chain 3 (LC3)-positive area was co-localized with the Wilms tumor 1 (WT1)-positive area on immunofluorescence microscopy, which suggested that autophagy occurred in the podocytes of patients with MCNS. The number of autophagic vacuoles in the podocytes was significantly correlated with the podocyte FPE score (r = -0.443, p = 0.004), the amount of proteinuria (r = 0.334, p = 0.033), and the level of serum albumin (r = -0.317, p = 0.043) in patients with MCNS. The FPE score was a significant determinant for autophagy after adjusting for the age in a multiple regression analysis in MCNS patients (p = 0.0456). However, such correlations were not observed in patients with IMN or in control subjects. In conclusion, the results indicated that the autophagy of podocytes is associated with FPE and severe proteinuria in patients with MCNS. The mechanisms underlying the activation of autophagy in association with FPE in podocytes should be further investigated in order to elucidate the pathophysiology of MCNS.
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Abstract
Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a “double-edged sword”—exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.
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Atp6ap2 deletion causes extensive vacuolation that consumes the insulin content of pancreatic β cells. Proc Natl Acad Sci U S A 2019; 116:19983-19988. [PMID: 31527264 DOI: 10.1073/pnas.1903678116] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Pancreatic β cells store insulin within secretory granules which undergo exocytosis upon elevation of blood glucose levels. Crinophagy and autophagy are instead responsible to deliver damaged or old granules to acidic lysosomes for intracellular degradation. However, excessive consumption of insulin granules can impair β cell function and cause diabetes. Atp6ap2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy. Here, we show that Cre recombinase-mediated conditional deletion of Atp6ap2 in mouse β cells causes a dramatic accumulation of large, multigranular vacuoles in the cytoplasm, with reduction of insulin content and compromised glucose homeostasis. Loss of insulin stores and gigantic vacuoles were also observed in cultured insulinoma INS-1 cells upon CRISPR/Cas9-mediated removal of Atp6ap2. Remarkably, these phenotypic alterations could not be attributed to a deficiency in autophagy or acidification of lysosomes. Together, these data indicate that Atp6ap2 is critical for regulating the stored insulin pool and that a balanced regulation of granule turnover is key to maintaining β cell function and diabetes prevention.
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Liu J, Zhou Y, Liu Y, Li L, Chen Y, Liu Y, Feng Y, Yosypiv IV, Song R, Peng H. (Pro)renin receptor regulates lung development via the Wnt/β-catenin signaling pathway. Am J Physiol Lung Cell Mol Physiol 2019; 317:L202-L211. [PMID: 31042081 PMCID: PMC6734386 DOI: 10.1152/ajplung.00295.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 02/01/2019] [Accepted: 04/28/2019] [Indexed: 11/22/2022] Open
Abstract
The (pro)renin receptor [(P)RR] binds to prorenin to activate the renin-angiotensin system and is essential for the development of many different organ systems. Whether the (P)RR also plays a role in lung development is unknown. Immunostaining was used to determine the spatial-temporal distribution of (P)RR in the embryonic, postnatal, and adult lungs. We created a lung-specific (P)RR knockout mouse [Foxd1cre/+-(P)RRflox/flox] and assessed changes in lung morphology, cell proliferation, and apoptosis using immunohistochemistry and TUNEL staining. (P)RR function was confirmed by using siRNA to knock down (P)RR in human bronchial epithelial cells (HBECs) and then using the CCK-8 assay and flow cytometry to assess cell proliferation and apoptosis. Gene expression changes after knockdown were assessed by RT-PCR and Western blotting. (P)RR is expressed in the club cells of the bronchial epithelium, and expression increases throughout development. Lung-specific (P)RR knockout disrupted branching morphogenesis, leading to lung hypoplasia and neonatal mortality. These defects were associated with increased apoptosis and decreased proliferation of the pulmonary epithelial and mesenchymal cells and may be mediated by downregulation of Wnt11, β-catenin, and Axin2. (P)RR regulates lung development through canonical Wnt/β-catenin signaling and may present a new target for strategies to treat lung hypoplasia.
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Affiliation(s)
- Jie Liu
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yafan Zhou
- Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, China
| | - Yalan Liu
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lei Li
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Chen
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yali Liu
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yumei Feng
- Department of Pharmacology, Center for Cardiovascular Research, University of Nevada School of Medicine, Reno, Nevada
| | - Ihor V Yosypiv
- Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana
| | - Renfang Song
- Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana
| | - Hua Peng
- Department of Pediatrics, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Foco L, Pattaro C. Genetics of Blood Pressure Regulation: Possible Paths in the Labyrinth. Am J Kidney Dis 2019; 74:421-424. [PMID: 31221530 DOI: 10.1053/j.ajkd.2019.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/03/2019] [Indexed: 11/11/2022]
Affiliation(s)
- Luisa Foco
- Eurac Research, Institute for Biomedicine, Bolzano, Italy
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Hsu YH, Chuang HC, Lee YH, Lin YF, Chiu YJ, Wang YL, Wu MS, Chiu HW. Induction of Fibrosis and Autophagy in Kidney Cells by Vinyl Chloride. Cells 2019; 8:cells8060601. [PMID: 31212930 PMCID: PMC6627785 DOI: 10.3390/cells8060601] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 02/07/2023] Open
Abstract
Vinyl chloride (VC) is a noninfective occupational risk factor. It is found in industrial chemicals, volatile organic compounds, cigarette smoke ingredients, etc. It is a kind of toxic gas that causes many diseases. VC exposure causes an increased risk of liver fibrosis and can result in angiosarcoma of the liver. Previous studies have shown that high-doses of VC exposure in mice resulted in acute death with marked tubular necrosis of the renal cortex. In this study, we assessed the nephrotoxicity of VC in vitro and in vivo. As a result, we demonstrated that VC induced fibrosis-associated protein expression, such as connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and collagen 1, and autophagy-associated protein expression, such as Beclin 1 and LC3-II, in kidney cells. The beclin1 siRNA experiments found that autophagy inhibited VC-induced fibrosis. Blood urea nitrogen (BUN) and creatinine levels were increased after VC treatment. Furthermore, VC caused glomerulosclerosis and tubular injury in mouse kidney tissues. Kidney tissue sections showed that VC induced fibrosis and autophagy in mouse kidney tissues. In summary, the results of VC-induced fibrosis suggest that autophagy plays an important role in kidney damage. VC may cause nephrotoxicity, and the results illustrate the importance of considering the toxicological hazards of VC in kidney cells.
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Affiliation(s)
- Yung-Ho Hsu
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Hsiao-Chi Chuang
- School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- School of Public Health, College of Public Health, Taipei Medical University, Taipei 11031, Taiwan.
| | - Yu-Hsuan Lee
- Department of Food Safety/Hygiene &Risk Management, College of Medicine, National Cheng Kung University, Tainan 70430, Taiwan.
| | - Yuh-Feng Lin
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Yu-Jhe Chiu
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Yung-Li Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Hui-Wen Chiu
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
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