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Rani P, Koulmane Laxminarayana SL, Swaminathan SM, Nagaraju SP, Bhojaraja MV, Shetty S, Kanakalakshmi ST. TGF-β: elusive target in diabetic kidney disease. Ren Fail 2025; 47:2483990. [PMID: 40180324 PMCID: PMC11980245 DOI: 10.1080/0886022x.2025.2483990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/17/2025] [Accepted: 03/14/2025] [Indexed: 04/05/2025] Open
Abstract
Transforming growth factor-beta (TGF-β), a cytokine with near omnipresence, is an integral part of many vital cellular processes across the human body. The family includes three isoforms: Transforming growth factor-beta 1, 2, and 3. These cytokines play a significant role in the fibrosis cascade. Diabetic kidney disease (DKD), a major complication of diabetes, is increasing in prevalence daily, and the classical diagnosis of diabetes is based on the presence of albuminuria. The occurrence of nonalbuminuric DKD has provided new insight into the pathogenesis of this disease. The emphasis on multifactorial pathways involved in developing DKD has highlighted some markers associated with tissue fibrosis. In diabetic nephropathy, TGF-β is significantly involved in its pathology. Its presence in serum and urine means that it could be a diagnostic tool while its regulation provides potential therapeutic targets. Completely blocking TGF-β signaling could reach untargeted regions and cause unanticipated effects. This paper reviews the basic details of TGF-β as a cytokine, its role in DKD, and updates on research carried out to validate its candidacy.
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Affiliation(s)
- Priya Rani
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | | | - Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | | | - Sahana Shetty
- Department of Endocrinology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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Wang Y, He W, Ren P, Zhao L, Zheng D, Jin J. Carthamin yellow-loaded glycyrrhetinic acid liposomes alleviate interstitial fibrosis in diabetic nephropathy. Ren Fail 2025; 47:2459356. [PMID: 39904762 PMCID: PMC11800343 DOI: 10.1080/0886022x.2025.2459356] [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: 05/27/2024] [Revised: 01/08/2025] [Accepted: 01/22/2025] [Indexed: 02/06/2025] Open
Abstract
OBJECTIVES To investigate the therapeutic efficacy of Carthamin yellow (CY)-loaded glycyrrhetinic acid (GA) liposomes in treating diabetic nephropathy (DN), particularly in alleviating renal interstitial fibrosis and improving kidney function. METHODS CY-loaded GA liposomes were prepared and characterized for structural stability and controlled release. DN rat models were treated with CY-loaded GA liposomes, and kidney pathology, function, collagen deposition, and TGF-β1 expression were evaluated. The effects of CY-loaded GA liposomes were compared to Vitamin E and CY alone. In vitro experiments with TGF-β1-stimulated human renal interstitial fibroblasts (hRIFs) examined the effects of CY-loaded GA liposomes on cell proliferation and the expression of fibrotic markers. Mechanistic studies assessed the role of the TGFBR1/Smad2/Smad3 pathway using TGFBR1 overexpression experiments. RESULTS The CY-loaded GA liposomes exhibited a stable structure and controlled release profile. In DN rats, treatment with CY-loaded GA liposomes significantly alleviated kidney damage, improved kidney function, reduced collagen deposition and fibrosis, and downregulated TGF-β1 expression, showing superior effects compared to Vitamin E or CY alone. In TGF-β1-stimulated hRIFs, CY-loaded GA liposomes effectively suppressed cell proliferation and reduced the expression of Cyclin D1, PCNA, fibronectin, and collagen I. The inhibitory effects were stronger than CY alone and were mediated by the inactivation of the TGFBR1/Smad2/Smad3 pathway, as confirmed by TGFBR1 overexpression studies. CONCLUSIONS CY-loaded GA liposomes demonstrated significant therapeutic efficacy in alleviating renal interstitial fibrosis in DN by targeting the TGFBR1/Smad2/Smad3 pathway. This novel drug delivery system provides a promising approach for the treatment of DN.
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Affiliation(s)
- Yifei Wang
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Wenfang He
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Peiyao Ren
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
| | - Li Zhao
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Danna Zheng
- Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Juan Jin
- Department of Nephrology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
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Hu X, Chen W, Yang M, Li M, Li X, Ouyang S. IGFBP5 promotes EndoMT and renal fibrosis through H3K18 lactylation in diabetic nephropathy. Cell Mol Life Sci 2025; 82:215. [PMID: 40423799 PMCID: PMC12116956 DOI: 10.1007/s00018-025-05718-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 03/25/2025] [Accepted: 04/16/2025] [Indexed: 05/28/2025]
Abstract
OBJECTIVE Diabetic nephropathy (DN) is an important complication in diabetic patients that severely impacts their quality of life and life expectancy. Although metabolic and inflammatory responses induced by hyperglycemia are considered the primary pathogenic factors of DN, the specific molecular mechanisms involved remain unclear. Here, we investigated the role of insulin-like growth factor-binding protein 5 (IGFBP5) in DN using in vitro cell experiments and mouse models. METHODS We assessed the effects of high-glucose conditions on IGFBP5 expression in glomerular endothelial cells and evaluated its regulatory effects on glycolysis, NLRP3 inflammasome activation, endothelial‒mesenchymal transition (EndoMT), and histone lactylation via the suppression of IGFBP5. Furthermore, we evaluated the effects of IGFBP5 on renal fibrosis and confirmed its regulatory mechanisms in DN model mice. RESULTS Knockdown of IGFBP5 inhibited high glucose-induced EndoMT in glomerular endothelial cells, which could also be suppressed by the NLRP3 inflammasome inhibitor MCC950. In addition, silencing of IGFBP5 decreased glycolytic activity and histone lactylation, thereby inhibiting the activation of the NLRP3 inflammasome and EndoMT. Furthermore, in mouse models of DN, IGFBP5 knockdown alleviated renal fibrosis and reduced glycolysis, histone lactylation, NLRP3 inflammasome activation and EndoMT. CONCLUSIONS IGFBP5 promotes NLRP3 inflammasome-induced EndoMT and renal fibrosis by regulating glycolysis-mediated histone lactylation, accelerating the progression of DN. These findings provide a new potential therapeutic target for DN.
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Affiliation(s)
- Xiaofang Hu
- Hunan Normal University Health Science Center, Changsha, 410013, Hunan, People's Republic of China
| | - Wei Chen
- Hunan Normal University Health Science Center, Changsha, 410013, Hunan, People's Republic of China
| | - Ming Yang
- Department of Nephrology, Zhuzhou Central Hospital, Zhuzhou, 412007, People's Republic of China
| | - Mengwei Li
- Hunan Normal University Health Science Center, Changsha, 410013, Hunan, People's Republic of China
| | - Xiangyi Li
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61 Jie-Fang West Road, Fu-Rong District, Changsha, 410005, Hunan, People's Republic of China
| | - Shaxi Ouyang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61 Jie-Fang West Road, Fu-Rong District, Changsha, 410005, Hunan, People's Republic of China.
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Jiang L, Jian J, Sai X, Wu X. Revealing VCAN as a Potential Common Diagnostic Biomarker of Renal Tubules and Glomerulus in Diabetic Kidney Disease Based on Machine Learning, Single-Cell Transcriptome Analysis and Mendelian Randomization. Diabetes Metab J 2025; 49:407-420. [PMID: 39849979 PMCID: PMC12086553 DOI: 10.4093/dmj.2024.0233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 09/07/2024] [Indexed: 01/25/2025] Open
Abstract
BACKGRUOUND Diabetic kidney disease (DKD) is recognized as a significant complication of diabetes mellitus and categorized into glomerular DKDs and tubular DKDs, each governed by distinct pathological mechanisms and biomarkers. METHODS Through the identification of common features observed in glomerular and tubular lesions in DKD, numerous differentially expressed gene were identified by the machine learning, single-cell transcriptome and mendelian randomization. RESULTS The diagnostic markers versican (VCAN) was identified, offering supplementary options for clinical diagnosis. VCAN significantly highly expressed in glomerular parietal epithelial cell and proximal convoluted tubular cell. It was mainly involved in the up-regulation of immune genes and infiltration of immune cells like mast cell. Mendelian randomization analysis confirmed that serum VCAN protein levels were a risky factor for DKD, while there was no reverse association. It exhibited the good diagnostic potential for estimated glomerular filtration rate and proteinuria in DKD. CONCLUSION VCAN showed the prospects into DKD pathology and clinical indicator.
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Affiliation(s)
- Li Jiang
- Diabetes Department of Integrated Chinese and Western Medicine, China National Center for Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jie Jian
- Mental Health Center of Dongcheng District, Beijing, China
| | - Xulin Sai
- Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Xiai Wu
- Diabetes Department of Integrated Chinese and Western Medicine, China National Center for Integrated Traditional Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing, China
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Rykova EY, Klimontov VV, Shmakova E, Korbut AI, Merkulova TI, Kzhyshkowska J. Anti-Inflammatory Effects of SGLT2 Inhibitors: Focus on Macrophages. Int J Mol Sci 2025; 26:1670. [PMID: 40004134 PMCID: PMC11854991 DOI: 10.3390/ijms26041670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/04/2025] [Accepted: 02/06/2025] [Indexed: 02/21/2025] Open
Abstract
A growing body of evidence indicates that nonglycemic effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors play an important role in the protective effects of these drugs in diabetes, chronic kidney disease, and heart failure. In recent years, the anti-inflammatory potential of SGLT2 inhibitors has been actively studied. This review summarizes results of clinical and experimental studies on the anti-inflammatory activity of SGLT2 inhibitors, with a special focus on their effects on macrophages, key drivers of metabolic inflammation. In patients with type 2 diabetes, therapy with SGLT2 inhibitors reduces levels of inflammatory mediators. In diabetic and non-diabetic animal models, SGLT2 inhibitors control low-grade inflammation by suppressing inflammatory activation of tissue macrophages, recruitment of monocytes from the bloodstream, and macrophage polarization towards the M1 phenotype. The molecular mechanisms of the effects of SGLT2 inhibitors on macrophages include an attenuation of inflammasome activity and inhibition of the TLR4/NF-κB pathway, as well as modulation of other signaling pathways (AMPK, PI3K/Akt, ERK 1/2-MAPK, and JAKs/STAT). The review discusses the state-of-the-art concepts and prospects of further investigations that are needed to obtain a deeper insight into the mechanisms underlying the effects of SGLT2 inhibitors on the molecular, cellular, and physiological levels.
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Affiliation(s)
- Elena Y. Rykova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
| | - Vadim V. Klimontov
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Elena Shmakova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia
| | - Anton I. Korbut
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Research Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), Timakov Str. 2, 630060 Novosibirsk, Russia
| | - Tatyana I. Merkulova
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
| | - Julia Kzhyshkowska
- Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia; (E.Y.R.); (V.V.K.); (E.S.); (A.I.K.); (T.I.M.)
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
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Nadendla RR, Khairunnisa K, Aziz N, Pyne C, Panigrahy UP, Wal P, Kulkarni MH, Rasheed A. An Updated Review on Diabetic Nephropathy: Potential Mechanisms, Biomarkers, Therapeutic Targets and Interventional Therapies. Curr Diabetes Rev 2025; 21:e240624231266. [PMID: 38919001 DOI: 10.2174/0115733998291920240611063402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 06/27/2024]
Abstract
BACKGROUND Diabetic nephropathy (DN), the primary risk factor for end-stage kidney disease (ESKD) that requires dialysis or renal transplantation, affects up to 50% of individuals with diabetes. OBJECTIVE In this article, potential mechanisms, biomarkers, and possible therapeutic targets will be discussed, as well as their interventional therapies. METHODS A literature review was done from databases like Google Scholar, PUBMEDMEDLINE, and Scopus using standard keywords "Diabetic Nephropathy," "Biomarkers," "Pathophysiology," "Cellular Mechanism," "Cell Therapy," "Treatment Therapies" from 2010- 2023. It has been studied that metabolic as well as hemodynamic pathways resulting from hyperglycemia act as mediators for renal disease. RESULTS We identified 270 articles, of which 210 were reviewed in full-text and 90 met the inclusion criteria. Every therapy regimen for the prevention and treatment of DN must include the blocking of ANG-II action. By reducing inflammatory and fibrotic markers brought on by hyperglycemia, an innovative approach to halting the progression of diabetic mellitus (DN) involves combining sodium-glucose cotransporter-2 inhibitors with renin-angiotensin-aldosterone system blockers. When compared to taking either medicine alone, this method works better. AGEs, protein kinase C (PKC), and the renin-angiotensin aldosterone system (RAAS) are among the components that are inhibited in DN management strategies. CONCLUSION Thus, it can be concluded that the multifactorial condition of DN needs to be treated at an early stage. Novel therapies with a combination of cell therapies and diet management are proven to be effective in the management of DN.
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Affiliation(s)
- Rama Rao Nadendla
- Chalapathi Institute of Pharmaceutical Sciences, Guntur, Andhra Pradesh, India
| | | | - Namra Aziz
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Chandana Pyne
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | - Uttam Prasad Panigrahy
- Faculty of Pharmaceutical Science, Assam Downtown University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, India
| | - Pranay Wal
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
| | | | - Azhar Rasheed
- PSIT-Pranveer Singh Institute of Technology (Pharmacy), NH-19, Kanpur-209305, UP, India
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Zhao Y, Wang Z, Ren J, Chen H, Zhu J, Zhang Y, Zheng J, Cao S, Li Y, Liu X, An N, Ban T, Yang B, Zhang Y. The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrin β1/TGFβ signaling. Front Med 2024; 18:1068-1086. [PMID: 39432186 DOI: 10.1007/s11684-024-1077-3] [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: 11/09/2023] [Accepted: 03/18/2024] [Indexed: 10/22/2024]
Abstract
Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.
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Affiliation(s)
- Yixiu Zhao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Zhiqi Wang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Jing Ren
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Huan Chen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Jia Zhu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Yue Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Jiangfei Zheng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Shifeng Cao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Yanxi Li
- College of Basic Medicine, Harbin Medical University, Harbin, 150081, China
| | - Xue Liu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Na An
- Heilongjiang Medical Academy, Harbin Medical University, Harbin, 150081, China
| | - Tao Ban
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China
| | - Baofeng Yang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China.
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin, 150081, China.
| | - Yan Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
- National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin, 150081, China.
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Li Y, Wang J. Possible mechanism for the protective effect of active ingredients of astragalus membranaceus on diabetes nephropathy. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:1276-1284. [PMID: 38856077 DOI: 10.1080/10286020.2024.2364350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 06/02/2024] [Indexed: 06/11/2024]
Abstract
Astragali Radix (AR), a common traditional Chinese medicinal herb, exhibits protective effects on diabetic nephropathy (DN) in extensive researches. Aticles focusing on AR in PubMed were collected and reviewed in order to summarize the latest pharmacological effects on DN. The action mechanisms for protectiving effects of AR were associated with regulation of anti-fibrosis, anti-inflammation, anti-oxidative stress, anti-podocyte apoptosis, restoration of mitochondrial function, restoration of endothelial function in diabetes nephropathy experimental models. Consequently, AR hold promise as potential novel therapeutics for the treatment of DN.
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Affiliation(s)
- Yu Li
- Department of Nephropathy, Luohu Hospital of Traditional Chinese Medicine, Shenzhen518001, China
| | - Jing Wang
- Department of Nephropathy, Luohu Hospital of Traditional Chinese Medicine, Shenzhen518001, China
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Huang J, Liu Y, Shi M, Zhang X, Zhong Y, Guo S, Ma Y, Pan L, Yang F, Wang Y. Empagliflozin attenuating renal interstitial fibrosis in diabetic kidney disease by inhibiting lymphangiogenesis and lymphatic endothelial-to-mesenchymal transition via the VEGF-C/VEGFR3 pathway. Biomed Pharmacother 2024; 180:117589. [PMID: 39418962 DOI: 10.1016/j.biopha.2024.117589] [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: 07/13/2024] [Revised: 10/04/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024] Open
Abstract
Renal interstitial fibrosis (RIF) is a significant pathological change in diabetic kidney disease (DKD) that can be induced by endothelial-to-mesenchymal transition (EndMT). Lymphangiogenesis, mediated by the vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) pathway, plays a crucial role in the development of RIF in DKD. Although numerous studies have demonstrated the efficacy of empagliflozin in treating renal injury, its effects on lymphangiogenesis in DKD-related RIF and the underlying mechanisms remain unclear. In the present study, significant lymphangiogenesis was assessed in the renal interstitium of patients with DKD. We subsequently explored the relationship between DKD-related RIF and lymphangiogenesis in mouse models, high-glucose (HG)-stimulated renal HK-2 cell lines, and human lymphatic endothelial cells (hLECs). Additionally, we evaluated the effects of empagliflozin on these processes. The results revealed that HG induces lymphangiogenesis, which exacerbates RIF by promoting inflammatory responses. Furthermore, hLECs directly contributed to the progression of DKD-related RIF through EndMT. Further analysis revealed that tubular epithelial cells (TECs) act as effector cells for VEGF-C, with the epithelial-to-mesenchymal transition (EMT) of TECs occurring concurrently with the EndMT of lymphatic vessels. Empagliflozin inhibited RIF in DKD by suppressing the VEGF-C/VEGFR3 pathway and reducing lymphangiogenesis. In conclusion, this study elucidates the interplay between lymphangiogenesis, EndMT, and RIF in DKD and provides new insights into the mechanism by which empagliflozin treats DKD.
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Affiliation(s)
- Jiaan Huang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, No.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China
| | - Yan Liu
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, No.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China
| | - Mengting Shi
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Acupuncture and moxibustion and Massage College of Hebei University of Chinese Medicine, No.3 Xingyuan Road, Luquan District, Shijiazhuang 050200, China
| | - Xiaoyun Zhang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China
| | - Yan Zhong
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China
| | - Shuai Guo
- The Third Hospital of Hebei Medical University, Shijiazhuang 050200, China
| | - Yun Ma
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China
| | - Limin Pan
- Hebei Provincial Hospital of Traditional Chinese Medicine, Shijiazhuang 050200, China
| | - Fan Yang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, No.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China.
| | - Yuehua Wang
- Hebei Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Liver and Kidney Diseases, Shijiazhuang 05000, China; Hebei University of Traditional Chinese Medicine, No.326, Xinshi South Road, Qiaoxi District, Shijiazhuang 05000, China; The Second Affiliated Hospital of Hebei University of Traditional Chinese Medicine, Dingzhou 073000, China.
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Lin L, Huang S, Lin X, Liu X, Xu X, Li C, Chen P. Upregulation of Metrnl improves diabetic kidney disease by inhibiting the TGF-β1/Smads signaling pathway: A potential therapeutic target. PLoS One 2024; 19:e0309338. [PMID: 39190657 PMCID: PMC11349091 DOI: 10.1371/journal.pone.0309338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/08/2024] [Indexed: 08/29/2024] Open
Abstract
PURPOSE This study comprises an investigation of the role of meteorin-like (Metrnl) in an experimental model of diabetic kidney disease (DKD). METHODS Twenty-four db/db mice were randomly assigned to one of the following groups: DKD, DKD + Metrnl-/-, and DKD + Metrnl+/+. Plasma Metrnl concentrations were measured using ELISA. Kidney tissues were examined via western blotting, qRT-PCR, and immunohistochemistry to determine the expression levels of inflammatory factors. Electron microscopy was employed to observe stained kidney sections. RESULTS Compared with the NC group, FBG, BW, and UACR were elevated in the DKD and Metrnl-/- groups, with severe renal pathological injury, decreased serum Metrnl concentration, decreased renal Metrnl expression, and increased expression levels of TNF-α, TGF-β1, TGF-R1, pSmad2, pSmad3, and α-SMA. In contrast, the Metrnl+/+ group showed decreased FBG and UACR, BUN, TC and TG, increased HDL-C and serum Metrnl concentration, increased renal Metrnl expression, and decreased expression of TNF-α, TGF-β1, TGF-R1, pSmad2, pSmad3, and α-SMA, compared to the DKD and Metrnl-/- groups. A Pearson bivariate correlation analysis revealed a negative correlation between UACR and Metrnl, and a positive correlation between UACR and TGF-β1. CONCLUSION Upregulation of renal Metrnl expression can improve renal injury by downregulating the expression of molecules in the TGF-β1/Smads signaling pathway in the renal tissues of type 2 diabetic mice; and by reducing the production of fibrotic molecules such as α-SMA.
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Affiliation(s)
- Lu Lin
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Shulin Huang
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Xin Lin
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Xiaoling Liu
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Xiangjin Xu
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Chunmei Li
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
| | - Pin Chen
- 900TH Hospital of Joint Logistic Support Force (Fuzong Clinical Medical College of Fujian Medical University), Fuzhou, China
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Wu C, Tang H, Cui X, Li N, Fei J, Ge H, Wu L, Wu J, Gu HF. A single-cell profile reveals the transcriptional regulation responded for Abelmoschus manihot (L.) treatment in diabetic kidney disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 130:155642. [PMID: 38759315 DOI: 10.1016/j.phymed.2024.155642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/08/2024] [Accepted: 04/13/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Huangkui capsule (HKC), as an ethanol extract of Abelmoschus manihot (L.), has a significant efficacy in treatment of the patients with diabetic kidney disease (DKD). The bioactive ingredients of HKC mainly include the flavonoids such as rutin, hyperoside, hibifolin, isoquercetin, myricetin, quercetin and quercetin-3-O-robinobioside. PURPOSE To explore the molecular mechanisms of A. manihot in treatment of DKD. STUDY DESIGN A single-cell RNA sequencing analysis of kidneys in db/db mice with and without HKC administration. METHODS Urinary biochemical and histopathological examination in C57BL/6 and db/db mice of DKD and HKC groups was done. Single-cell RNA sequencing pipeline was then performed. The regulatory mechanisms of seven flavonoids in HKC were revealed by cell communication, prediction of transcription factor regulatory network, and molecular docking. RESULTS By constructing ligand-receptor regulatory network and performing molecular docking between 75 receptors with different activities and seven flavonoids. 11 key receptors in 4 cell types (segment 3 proximal convoluted tubular cell, ascending limbs of the loop of Henle, distal convoluted tubule, and T cell) in kidneys were found to be directly interacted with HKC. The interactions regulated 8 downstream regulons. The docking receptors in T cell led to transcriptional event differences in the regulons such as Cebpb, Rel, Tbx21 and Klf2 and consequently affected the activation, differentiation, and infiltration of T cell, while the receptors Tgfbr1 and Ldlr in stromal cells of kidneys were closely associated with the downstream transcriptional events of renal injury and proteinuria in DKD. CONCLUSION The current study provides novel information of the key receptors and regulons in renal cells for a better understanding of the cell type specific molecular mechanisms of A. manihot in treatment of DKD.
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Affiliation(s)
- Chenhua Wu
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China; Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Haitao Tang
- Suzhong Pharmaceutical Research Institute, Nanjing, Jiangsu Province, 210018, China
| | - Xu Cui
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Nan Li
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, 210029, China
| | - Jingjin Fei
- Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China
| | - Haitao Ge
- Suzhong Pharmaceutical Research Institute, Nanjing, Jiangsu Province, 210018, China
| | - Liang Wu
- Jiangsu Key Laboratory of Drug Screening, Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Jie Wu
- Laboratory of Minigene Pharmacy, School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu Province, 211198, China.
| | - Harvest F Gu
- Laboratory of Molecular Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China.
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Li J, Pang Q, Huang X, Jiang H, Tang G, Yan H, Guo Y, Yan X, Li L, Zhang H. 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione isolated from Averrhoa carambola L. root inhibits high glucose-induced EMT in HK-2 cells through targeting the regulation of miR-21-5p/Smad7 signaling pathway. Biomed Pharmacother 2024; 172:116280. [PMID: 38368837 DOI: 10.1016/j.biopha.2024.116280] [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: 12/01/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 02/20/2024] Open
Abstract
OBJECTIVE 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1, 4-Dione (DMDD) isolated from Averrhoa carambola L. root, has been proven therapeutic effects on diabetic kidney disease (DKD). This research aims to assess DMDD's effects on DKD and to investigate its underlying mechanisms, to establish DMDD as a novel pharmaceutical agent for DKD treatment. METHODS The human renal tubular epithelial (HK-2) cells were induced by high glucose (HG) to mimic DKD and followed by DMDD treatment. The cytotoxicity of DMDD was assessed using the Cell Counting Kit-8 (CCK-8) assay. The migratory capacity of HK-2 cells was evaluated through transwell and scratch-wound assays. To investigate the effect of Smad7 and miR-21-5p, lentiviral transfection was employed in HK-2 cells. Additionally, the expression of proteins related to epithelial-mesenchymal transition (EMT) and TGFβ1/Smad2/3 pathway was checked by QRT-PCR, Western blot, and immunofluorescence techniques. RESULTS This study has shown that DMDD significantly suppresses cell migration and the expression of Vimentin, α-SMA, TGFβ1, and p-Smad2/3 in HK-2 cells under HG conditions. Concurrently, DMDD enhances the protein expression of E-cadherin and Smad7. Intriguingly, the therapeutic effect of DMDD was abrogated upon Smad7 silencing. Further investigations revealed that DMDD effectively inhibits miR-21-5p expression, which is upregulated by HG. Downregulation of miR-21-5p inhibits the activation of the TGFβ1/Smad2/3 pathway and EMT induced by HG. In contrast, overexpression of miR-21-5p negates DMDD's therapeutic benefits. CONCLUSION DMDD mitigates EMT in HG-induced HK-2 cells by modulating the miR-21-5p/Smad7 pathway, thereby inhibiting renal fibrosis in DKD. These findings suggest that DMDD holds promise as a potential therapeutic agent for DKD.
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Affiliation(s)
- Jingyi Li
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Qiuling Pang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaoman Huang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Huixian Jiang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Ganling Tang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Hui Yan
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Yanxiang Guo
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Xiaoyi Yan
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Lang Li
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China; Guangxi Key Laboratory of Precision Medicine for Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Nanning, Guangxi 530021, China
| | - Hongliang Zhang
- Pharmacy Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
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Adzraku SY, Cao C, Zhou Q, Yuan K, Hao X, Li Y, Yuan S, Huang Y, Xu K, Qiao J, Ju W, Zeng L. Endothelial Robo4 suppresses endothelial-to-mesenchymal transition induced by irradiation and improves hematopoietic reconstitution. Cell Death Dis 2024; 15:159. [PMID: 38383474 PMCID: PMC10881562 DOI: 10.1038/s41419-024-06546-4] [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: 08/24/2023] [Revised: 02/04/2024] [Accepted: 02/07/2024] [Indexed: 02/23/2024]
Abstract
Bone marrow ablation is routinely performed before hematopoietic stem cell transplantation (HSCT). Hematopoietic stem and progenitor cells (HSPCs) require a stable bone marrow microenvironment to expand and refill the peripheral blood cell pool after ablation. Roundabout guidance receptor 4 (Robo4) is a transmembrane protein exclusive to endothelial cells and is vital in preserving vascular integrity. Hence, the hypothesis is that Robo4 maintains the integrity of bone marrow endothelial cells following radiotherapy. We created an endothelial cell injury model with γ-radiation before Robo4 gene manipulation using lentiviral-mediated RNAi and gene overexpression techniques. We demonstrate that Robo4 and specific mesenchymal proteins (Fibronectin, Vimentin, αSma, and S100A4) are upregulated in endothelial cells exposed to irradiation (IR). We found that Robo4 depletion increases the expression of endoglin (CD105), an auxiliary receptor for the transforming growth factor (TGF-β) family of proteins, and promotes endothelial-to-mesenchymal transition (End-MT) through activation of both the canonical (Smad) and non-canonical (AKT/NF-κB) signaling pathways to facilitate Snail1 activation and its nuclear translocation. Endothelial Robo4 overexpression stimulates the expression of immunoglobulin-like adhesion molecules (ICAM-1 and VCAM-1) and alleviates irradiation-induced End-MT. Our coculture model showed that transcriptional downregulation of endothelial Robo4 reduces HSPC proliferation and increases HSC quiescence and apoptosis. However, Robo4 overexpression mitigated the damaged endothelium's suppressive effects on HSC proliferation and differentiation. These findings indicate that by controlling End-MT, Robo4 preserves microvascular integrity after radiation preconditioning, protects endothelial function, and lessens the inhibitory effect of damaged endothelium on hematopoietic reconstitution.
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Affiliation(s)
- Seyram Yao Adzraku
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Xuzhou Ruihu Health Management Consulting Co, Ltd, xuzhou, 221002, China
| | - Can Cao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Xuzhou Ruihu Health Management Consulting Co, Ltd, xuzhou, 221002, China
| | - Qi Zhou
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
- Xuzhou Ruihu Health Management Consulting Co, Ltd, xuzhou, 221002, China
| | - Ke Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Xiaowen Hao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yue Li
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Shengnan Yuan
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Yujin Huang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Kailin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China
| | - Jianlin Qiao
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China.
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China.
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
| | - Wen Ju
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China.
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China.
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
- Xuzhou Ruihu Health Management Consulting Co, Ltd, xuzhou, 221002, China.
| | - Lingyu Zeng
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, 221002, China.
- Key Laboratory of Bone Marrow Stem Cells, Jiangsu Province, Xuzhou, 221002, China.
- Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.
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Yao W, Tao R, Xu Y, Chen ZS, Ding X, Wan L. AR/RKIP pathway mediates the inhibitory effects of icariin on renal fibrosis and endothelial-to-mesenchymal transition in type 2 diabetic nephropathy. JOURNAL OF ETHNOPHARMACOLOGY 2024; 320:117414. [PMID: 37977422 DOI: 10.1016/j.jep.2023.117414] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 11/03/2023] [Accepted: 11/09/2023] [Indexed: 11/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Herba epimedium brevicornu maxim is traditionally known as a sexual enhancement, and has the effect of tonifying kidney yang. Icariin is a flavonoid extracted from epimedium brevicornu maxim, and has been shown to improve nephropathy disease. AIM OF THE STUDY This study investigated the possible role of icariin in regulating renal EndMT in type 2 diabetic nephropathy (T2DN). MATERIALS AND METHODS Male type 2 diabetic Sprague Dawley rats, Male D2.BKS(D)-Leprdb/J (db/db) mice, and mouse glomerular endothelial cells were utilized to evaluate the effect of icariin. Western blotting, Q-PCR, immunohistochemistry, H&E, Masson staining, immunofluorescence, and siRNA transfection, were performed in this study. RESULTS The inhibitory function of icariin in renal fibrosis and renal EndMT was verified in type 2 diabetic animals. Methyltestosterone suppressed renal fibrosis and EndMT in db/db mice. Androgen receptor (AR), the major receptor of testosterone, was upregulated by icariin. The AR antagonist MDV3100, blocked the inhibition by icariin in renal EndMT, revealing that icariin repressed renal EndMT by activating AR. In addition, icariin and methyltestosterone upregulated the Raf kinase inhibitor protein (RKIP) in db/db mice. Furthermore, siRNA-RKIP inhibited the effect of icariin on EndMT. The MEK/ERK pathway, as the downstream pathway of RKIP, was suppressed by icariin and methyltestosterone. Of note, the effect of icariin on the MEK/ERK pathway was abolished by MDV3100 or siRNA-RKIP. CONCLUSIONS These results supported that icariin targeted AR/RKIP/MEK/ERK pathway to suppress renal fibrosis and EndMT in T2DN.
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Affiliation(s)
- Wenhui Yao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Rongpin Tao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yue Xu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St. John's University, New York, NY, 11439, USA
| | - Xuansheng Ding
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China; Precision Medicine Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Lisheng Wan
- Department of Traditional Chinese Medicine, Shenzhen Children's Hospital, Shenzhen, China.
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15
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Yan X, Xia Y, Li B, Ye Z, Li L, Yuan T, Song B, Yu W, Rao T, Ning J, Lin F, Mei S, Mao Z, Zhou X, Li W, Cheng F. The SOX4/EZH2/SLC7A11 signaling axis mediates ferroptosis in calcium oxalate crystal deposition-induced kidney injury. J Transl Med 2024; 22:9. [PMID: 38169402 PMCID: PMC10763321 DOI: 10.1186/s12967-023-04793-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 12/09/2023] [Indexed: 01/05/2024] Open
Abstract
Epigenetic regulation is reported to play a significant role in the pathogenesis of various kidney diseases, including renal cell carcinoma, acute kidney injury, renal fibrosis, diabetic nephropathy, and lupus nephritis. However, the role of epigenetic regulation in calcium oxalate (CaOx) crystal deposition-induced kidney injury remains unclear. Our study demonstrated that the upregulation of enhancer of zeste homolog 2 (EZH2)-mediated ferroptosis facilitates CaOx-induced kidney injury. CaOx crystal deposition promoted ferroptosis in vivo and in vitro. Usage of liproxstatin-1 (Lip-1), a ferroptosis inhibitor, mitigated CaOx-induced kidney damage. Single-nucleus RNA-sequencing, RNA-sequencing, immunohistochemical and western blotting analyses revealed that EZH2 was upregulated in kidney stone patients, kidney stone mice, and oxalate-stimulated HK-2 cells. Experiments involving in vivo EZH2 knockout, in vitro EZH2 knockdown, and in vivo GSK-126 (an EZH2 inhibitor) treatment confirmed the protective effects of EZH2 inhibition on kidney injury and ferroptosis. Mechanistically, the results of RNA-sequencing and chromatin immunoprecipitation assays demonstrated that EZH2 regulates ferroptosis by suppressing solute carrier family 7, member 11 (SLC7A11) expression through trimethylation of histone H3 lysine 27 (H3K27me3) modification. Additionally, SOX4 regulated ferroptosis by directly modulating EZH2 expression. Thus, this study demonstrated that SOX4 facilitates ferroptosis in CaOx-induced kidney injury through EZH2/H3K27me3-mediated suppression of SLC7A11.
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Affiliation(s)
- Xinzhou Yan
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Yuqi Xia
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Bojun Li
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Zehua Ye
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Lei Li
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Tianhui Yuan
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Baofeng Song
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Weimin Yu
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Ting Rao
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Jinzhuo Ning
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Fangyou Lin
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China
| | - Shuqin Mei
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, People's Republic of China
| | - Zhiguo Mao
- Department of Nephrology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, 200003, People's Republic of China
| | - Xiangjun Zhou
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
| | - Wei Li
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital, Wuhan University, Wuhan, 430060, Hubei, People's Republic of China.
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Abstract
PURPOSE OF REVIEW Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity and mortality rates. Growing evidence indicates that common cellular and molecular mechanisms may drive fibrosis of diverse cause and affecting different organs. The scope of this review is to highlight recent findings in support for an important role of vascular endothelial cells in the pathogenesis of fibrosis, with a special focus on systemic sclerosis as a prototypic multisystem fibrotic disorder. RECENT FINDINGS Although transition of fibroblasts to chronically activated myofibroblasts is widely considered the central profibrotic switch, the endothelial cell involvement in development and progression of fibrosis has been increasingly recognized over the last few years. Endothelial cells can contribute to the fibrotic process either directly by acting as source of myofibroblasts through endothelial-to-myofibroblast transition (EndMT) and concomitant microvascular rarefaction, or indirectly by becoming senescent and/or secreting a variety of profibrotic and proinflammatory mediators with consequent fibroblast activation and recruitment of inflammatory/immune cells that further promote fibrosis. SUMMARY An in-depth understanding of the mechanisms underlying EndMT or the acquisition of a profibrotic secretory phenotype by endothelial cells will provide the rationale for novel endothelial cell reprogramming-based therapeutic approaches to prevent and/or treat fibrosis.
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Affiliation(s)
- Eloisa Romano
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Tan SK, Pinzon-Cortes JA, Cooper ME. Novel pharmacological interventions for diabetic kidney disease. Curr Opin Nephrol Hypertens 2024; 33:13-25. [PMID: 37889557 DOI: 10.1097/mnh.0000000000000935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden. RECENT FINDINGS We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets. SUMMARY Renal specific outcome trials have become more popular and are increasing the available armamentarium to diminish the progression of renal decline in patients at greater risk of end-stage kidney disease (ESKD) such as diabetic individuals. A combined pharmaceutical approach based on available rigorous studies should include RAAS blockade, SGLT2 inhibitors, nonsteroidal MRA and expectedly GLP1-RA on a personalized based-intervention. New specific trials designed to address renal outcomes will be needed for innovative therapies to conclude on their potential benefits in DKD.
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Affiliation(s)
- Seng Kiong Tan
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Diabetes Centre, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Jairo A Pinzon-Cortes
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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Yang J, Liu J, Liang J, Li F, Wang W, Chen H, Xie X. Epithelial-mesenchymal transition in age-associated thymic involution: Mechanisms and therapeutic implications. Ageing Res Rev 2023; 92:102115. [PMID: 37922996 DOI: 10.1016/j.arr.2023.102115] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/17/2023] [Accepted: 10/29/2023] [Indexed: 11/07/2023]
Abstract
The thymus is a critical immune organ with endocrine and immune functions that plays important roles in the physiological and pathological processes of the body. However, with aging, the thymus undergoes degenerative changes leading to decreased production and output of naive T cells and the secretion of thymic hormones and related cytokines, thereby promoting the occurrence and development of various age-associated diseases. Therefore, identifying essential processes that regulate age-associated thymic involution is crucial for long-term control of thymic involution and age-associated disease progression. Epithelial-mesenchymal transition (EMT) is a well-established process involved in organ aging and functional impairment through tissue fibrosis in several organs, such as the heart and kidney. In the thymus, EMT promotes fibrosis and potentially adipogenesis, leading to thymic involution. This review focuses on the factors involved in thymic involution, including oxidative stress, inflammation, and hormones, from the perspective of EMT. Furthermore, current interventions for reversing age-associated thymic involution by targeting EMT-associated processes are summarized. Understanding the key mechanisms of thymic involution through EMT as an entry point may promote the development of new therapies and clinical agents to reverse thymic involution and age-associated disease.
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Affiliation(s)
- Jiali Yang
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Juan Liu
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Jiayu Liang
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Fan Li
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Wenwen Wang
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China
| | - Huan Chen
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China.
| | - Xiang Xie
- The School of Basic Medical Sciences, Southwest Medical University, Luzhou, China; Public Center of Experimental Technology, Model Animal and Human Disease Research of Luzhou Key Laboratory, Southwest Medical University, Luzhou, China.
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Xue S, Li YX, Lu XX, Tang W. Dapagliflozin can alleviate renal fibrosis in rats with streptozotocin‑induced type 2 diabetes mellitus. Exp Ther Med 2023; 26:572. [PMID: 38023356 PMCID: PMC10652239 DOI: 10.3892/etm.2023.12271] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 08/14/2023] [Indexed: 12/01/2023] Open
Abstract
The aim of the present study was to explore the effects of Dapagliflozin on renal fibrosis in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats, and to determine the underlying mechanism of action. A total of 24 SPF male SD rats were randomly divided into 4 groups: A normal (Control) group, model group (STZ-induced T2DM rats), Dapagliflozin group (STZ-induced T2DM rats treated with 1 mg/kg Dapagliflozin), and a metformin group (STZ-induced T2DM rats treated with 200 mg/kg metformin), with 6 rats per a group. Peripheral blood and renal tissues were collected from these rats, and the renal indices of each group were examined. The fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), blood urea nitrogen (BUN), and serum creatinine (SCr) of rats were detected. After 24 h, the urine was collected and the urine protein levels were measured. Hematoxylin and eosin staining was used to detect histological changes in the rat kidney; Masson staining was used to observe the degree of fibrosis in rat renal tissues; and western blot was performed to determine the expression levels of α-smooth muscle actin (SMA), vimentin, E-cadherin, TGF-β1, Smad7, and p-Smad3 in rat renal tissues. Dapagliflozin effectively inhibited the increase in FBG and HbA1c levels in diabetic mice, reduced renal tissue damage, reduced the renal index values, reduced collagen deposition in the glomerulus and interstitial area, and reduced the proliferation of glomerular mesangial cells. In addition, Dapagliflozin significantly lowered the levels of BUN, SCr, and 24-h urine protein, decreased the protein expression of α-SMA, vimentin, TGF-β1, and p-Smad3, and increased the protein expression levels of E-cadherin and Smad7. Together, these results showed that Dapagliflozin alleviated renal fibrosis in STZ-induced T2DM rats, and its mechanism of action may be related to the inhibition of the TGF-β1/Smad pathway.
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Affiliation(s)
- Song Xue
- Department of Endocrinology, Shanghai Changzheng Hospital, Shanghai 200003, P.R. China
| | - Ying-Xuan Li
- Department of Endocrinology, Shanghai Gongli Hospital, Shanghai 200135, P.R. China
| | - Xiao-Xiao Lu
- Department of Endocrinology, Shanghai Zhoupu Hospital, Shanghai 201318, P.R. China
| | - Wei Tang
- Department of Endocrinology, Shanghai Changzheng Hospital, Shanghai 200003, P.R. China
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20
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Sung K, Chang H, Hsu N, Huang W, Lin Y, Yun C, Hsiao C, Hsu C, Tsai S, Chen Y, Tsai C, Su C, Hung T, Hou CJ, Yeh H, Hung C. Penalized Model-Based Unsupervised Phenomapping Unravels Distinctive HFrEF Phenotypes With Improved Outcomes Discrimination From Sacubitril/Valsartan Treatment Independent of MAGGIC Score. J Am Heart Assoc 2023; 12:e028860. [PMID: 37681571 PMCID: PMC10547272 DOI: 10.1161/jaha.122.028860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 07/26/2023] [Indexed: 09/09/2023]
Abstract
Background The angiotensin receptor-neprilysin inhibitor (LCZ696) has emerged as a promising pharmacological intervention against renin-angiotensin system inhibitor in reduced ejection fraction heart failure (HFrEF). Whether the therapeutic benefits may vary among heterogeneous HFrEF subgroups remains unknown. Methods and Results This study comprised a pooled 2-center analysis including 1103 patients with symptomatic HFrEF with LCZ696 use and another 1103 independent HFrEF control cohort (with renin-angiotensin system inhibitor use) matched for age, sex, left ventricular ejection fraction, and comorbidity conditions. Three main distinct phenogroup clusterings were identified from unsupervised machine learning using 29 clinical variables: phenogroup 1 (youngest, relatively lower diabetes prevalence, highest glomerular filtration rate with largest left ventricular size and left ventricular wall stress); phenogroup 2 (oldest, lean, highest diabetes and vascular diseases prevalence, lowest highest glomerular filtration rate with smallest left ventricular size and mass), and phenogroup 3 (lowest clinical comorbidity with largest left ventricular mass and highest hypertrophy prevalence). During the median 1.74-year follow-up, phenogroup assignment provided improved prognostic discrimination beyond Meta-Analysis Global Group in Chronic Heart Failure risk score risk score (all net reclassification index P<0.05) with overall good calibrations. While phenogroup 1 showed overall best clinical outcomes, phenogroup 2 demonstrated highest cardiovascular death and worst renal end point, with phenogroup 3 having the highest all-cause death rate and HF hospitalization among groups, respectively. These findings were broadly consistent when compared with the renin-angiotensin system inhibitor control as reference group. Conclusions Phenomapping provided novel insights on unique characteristics and cardiac features among patients with HFrEF with sacubitril/valsartan treatment. These findings further showed potentiality in identifying potential sacubitril/valsartan responders and nonresponders with improved outcome discrimination among patients with HFrEF beyond clinical scoring.
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Affiliation(s)
- Kuo‐Tzu Sung
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Institute of Clinical MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | | | - Nai‐Wei Hsu
- Department of Medical EducationVeterans General HospitalTaipeiTaiwan
| | - Wen‐Hung Huang
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Mackay Junior College of MedicineNursing and ManagementNew Taipei CityTaiwan
| | - Yueh‐Hung Lin
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Institute of Clinical MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Chun‐Ho Yun
- Mackay Junior College of MedicineNursing and ManagementNew Taipei CityTaiwan
- Division of RadiologyMacKay Memorial HospitalTaipeiTaiwan
| | - Chih‐Chung Hsiao
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
| | - Chien‐Yi Hsu
- Division of Cardiology and Cardiovascular Research Center, Department of Internal MedicineTaipei Medical University HospitalTaipeiTaiwan
| | - Shin‐Yi Tsai
- Johns Hopkins University Bloomberg School of Public HealthBaltimoreMD
| | - Ying‐Ju Chen
- Department of TelehealthMacKay Memorial HospitalTaipeiTaiwan
| | - Cheng‐Ting Tsai
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Mackay Junior College of MedicineNursing and ManagementNew Taipei CityTaiwan
| | - Cheng‐Huang Su
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
| | - Ta‐Chuan Hung
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Mackay Junior College of MedicineNursing and ManagementNew Taipei CityTaiwan
| | - Charles Jia‐Yin Hou
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
- Mackay Junior College of MedicineNursing and ManagementNew Taipei CityTaiwan
| | - Hung‐I Yeh
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew TaipeiTaiwan
| | - Chung‐Lieh Hung
- Division of Cardiology, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of TelehealthMacKay Memorial HospitalTaipeiTaiwan
- Institute of Biomedical SciencesMacKay Medical CollegeNew TaipeiTaiwan
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Guo W, Li H, Li Y, Kong W. Renal intrinsic cells remodeling in diabetic kidney disease and the regulatory effects of SGLT2 Inhibitors. Biomed Pharmacother 2023; 165:115025. [PMID: 37385209 DOI: 10.1016/j.biopha.2023.115025] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/11/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent complication of diabetes and a major secondary factor leading to end-stage renal disease. The kidney, a vital organ, is composed of a heterogeneous group of intrinsic cells, including glomerular endothelial cells, podocytes, mesangial cells, tubular epithelial cells, and interstitial fibroblasts. In the context of DKD, hyperglycemia elicits direct or indirect injury to these intrinsic cells, leading to their structural and functional changes, such as cell proliferation, apoptosis, and transdifferentiation. The dynamic remodeling of intrinsic cells represents an adaptive response to stimulus during the pathogenesis of diabetic kidney disease. However, the persistent stimulus may trigger an irreversible remodeling, leading to fibrosis and functional deterioration of the kidney. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of hypoglycemic drugs, exhibit efficacy in reducing blood glucose levels by curtailing renal tubular glucose reabsorption. Furthermore, SGLT2 inhibitors have been shown to modulate intrinsic cell remodeling in the kidney, ameliorate kidney structure and function, and decelerate DKD progression. This review will elaborate on the intrinsic cell remodeling in DKD and the underlying mechanism of SGLT2 inhibitors in modulating it from the perspective of the renal intrinsic cell, providing insights into the pathogenesis of DKD and the renal protective action of SGLT2 inhibitors.
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Affiliation(s)
- Wenwen Guo
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, Hubei 430022, China; Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, Hubei 430022, China
| | - Han Li
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, Hubei 430022, China; Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, Hubei 430022, China
| | - Yixuan Li
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, Hubei 430022, China; Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, Hubei 430022, China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, Hubei 430022, China; Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, Hubei 430022, China; Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, Hubei 430022, China.
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22
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Wu Q, Du X, Cheng J, Qi X, Liu H, Lv X, Gong X, Shao C, Wang M, Yue L, Yang X, Li S, Zhang Y, Li X, Yang H. PECAM-1 drives β-catenin-mediated EndMT via internalization in colon cancer with diabetes mellitus. Cell Commun Signal 2023; 21:203. [PMID: 37580771 PMCID: PMC10426208 DOI: 10.1186/s12964-023-01193-2] [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: 03/02/2023] [Accepted: 06/10/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is considered to be a risk factor in carcinogenesis and progression, although the biological mechanisms are not well understood. Here we demonstrate that platelet-endothelial cell adhesion molecule 1 (PECAM-1) internalization drives β-catenin-mediated endothelial-mesenchymal transition (EndMT) to link DM to cancer. METHODS The tumor microenvironment (TME) was investigated for differences between colon cancer with and without DM by mRNA-microarray analysis. The effect of DM on colon cancer was determined in clinical patients and animal models. Furthermore, EndMT, PECAM-1 and Akt/GSK-3β/β-catenin signaling were analyzed under high glucose (HG) and human colon cancer cell (HCCC) supernatant (SN) or coculture conditions by western and immunofluorescence tests. RESULTS DM promoted the progression and EndMT occurrence of colon cancer (CC). Regarding the mechanism, DM induced PECAM-1 defection from the cytomembrane, internalization and subsequent accumulation around the cell nucleus in endothelial cells, which promoted β-catenin entry into the nucleus, leading to EndMT occurrence in CC with DM. Additionally, Akt/GSK-3β signaling was enhanced to inhibit the degradation of β-catenin, which regulates the process of EndMT. CONCLUSIONS PECAM-1 defects and/or internalization are key events for β-catenin-mediated EndMT, which is significantly boosted by enhanced Akt/GSK-3β signaling in the DM-associated TME. This contributes to the mechanism by which DM promotes the carcinogenesis and progression of CC. Video Abstract.
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Affiliation(s)
- Qing Wu
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xingxing Du
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Jianing Cheng
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xiuying Qi
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Huan Liu
- Department of Humanities Foundation, Heilongjiang Nursing College, Harbin, China
| | - Xiaohong Lv
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xieyang Gong
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Changxin Shao
- Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Muhong Wang
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, China
| | - Luxiao Yue
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Xin Yang
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Shiyu Li
- Department of Anatomy, Harbin Medical University, Harbin, China
| | - Yafang Zhang
- Department of Anatomy, Harbin Medical University, Harbin, China.
| | - Xuemei Li
- Department of Anatomy, Harbin Medical University, Harbin, China.
| | - Huike Yang
- Department of Anatomy, Harbin Medical University, Harbin, China.
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Liu Z, Liu J, Wang W, An X, Luo L, Yu D, Sun W. Epigenetic modification in diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1133970. [PMID: 37455912 PMCID: PMC10348754 DOI: 10.3389/fendo.2023.1133970] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/30/2023] [Indexed: 07/18/2023] Open
Abstract
Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.
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Affiliation(s)
- Zhe Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Jiahui Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wanning Wang
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Weixia Sun
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
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24
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Wan X, Liao J, Lai H, Zhang S, Cui J, Chen C. Roles of microRNA-192 in diabetic nephropathy: the clinical applications and mechanisms of action. Front Endocrinol (Lausanne) 2023; 14:1179161. [PMID: 37396169 PMCID: PMC10309560 DOI: 10.3389/fendo.2023.1179161] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 05/25/2023] [Indexed: 07/04/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most common and intractable microvascular complications of diabetes worldwide, serving as the main cause of terminal renal disease. Due to the lack of early specific symptoms and diagnostic markers, DN severely threatens the sufferer's life. MicroRNA-192 (miR-192) was early identified in human renal cortical tissue and stored and excreted in urine as microvesicles. MiR-192 was found to be involved in the development of DN. For the first time, the present review summarized all the current evidence on the topic of the roles of miR-192 in DN. Finally, 28 studies (ten clinical trials and eighteen experimental studies) were eligible for thorough reviewing. Most of the clinical trials (7/10, 70%) indicated miR-192 might be a protective factor for DN development and progression, while the majority of experimental studies (14/18, 78%) suggested miR-192 might be a pathogenic factor for DN. Mechanistically, miR-192 interacts with various direct targeted proteins (i.e., ZEB1, ZEB2, SIP1, GLP1R, and Egr1) and signaling cascades (i.e., SMAD/TGF-β and PTEN/PI3K/AKT), together contribute to the pathogenesis of DN through epithelial-to-mesenchymal transition (EMT), extracellular matrix deposition, and fibrosis formation. The current review highlights the dual role of miR-192 in the development of DN. Low serum miR-192 expression could be applied for the early prediction of DN (the early stage of DN), while the high miR-192 level in renal tissues and urine may imply the progression of DN (the late stage of DN). Further investigations are still warranted to illustrate this inconsistent phenomenon, which may facilitate promoting the therapeutic applications of miR-192 in predicting and treating DN.
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Affiliation(s)
- Xiaoqing Wan
- Department of Nephrology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Jian Liao
- Department of Nephrology, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China
| | - Hongting Lai
- Clinical Medical College, Tianjin Medical University, Tianjin, China
| | - Shilong Zhang
- Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianling Cui
- Department of Nephrology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Chunyan Chen
- Department of Nephrology, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing, Zhejiang, China
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Phua TJ. Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis. FRONTIERS IN AGING 2023; 4:1196648. [PMID: 37384143 PMCID: PMC10293850 DOI: 10.3389/fragi.2023.1196648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/23/2023] [Indexed: 06/30/2023]
Abstract
Aging-related hypoxia, oxidative stress, and inflammation pathophysiology are closely associated with human age-related carcinogenesis and chronic diseases. However, the connection between hypoxia and hormonal cell signaling pathways is unclear, but such human age-related comorbid diseases do coincide with the middle-aging period of declining sex hormonal signaling. This scoping review evaluates the relevant interdisciplinary evidence to assess the systems biology of function, regulation, and homeostasis in order to discern and decipher the etiology of the connection between hypoxia and hormonal signaling in human age-related comorbid diseases. The hypothesis charts the accumulating evidence to support the development of a hypoxic milieu and oxidative stress-inflammation pathophysiology in middle-aged individuals, as well as the induction of amyloidosis, autophagy, and epithelial-to-mesenchymal transition in aging-related degeneration. Taken together, this new approach and strategy can provide the clarity of concepts and patterns to determine the causes of declining vascularity hemodynamics (blood flow) and physiological oxygenation perfusion (oxygen bioavailability) in relation to oxygen homeostasis and vascularity that cause hypoxia (hypovascularity hypoxia). The middle-aging hypovascularity hypoxia hypothesis could provide the mechanistic interface connecting the endocrine, nitric oxide, and oxygen homeostasis signaling that is closely linked to the progressive conditions of degenerative hypertrophy, atrophy, fibrosis, and neoplasm. An in-depth understanding of these intrinsic biological processes of the developing middle-aged hypoxia could provide potential new strategies for time-dependent therapies in maintaining healthspan for healthy lifestyle aging, medical cost savings, and health system sustainability.
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Affiliation(s)
- Teow J. Phua
- Molecular Medicine, NSW Health Pathology, John Hunter Hospital, Newcastle, NSW, Australia
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Eleftheriadis T, Pissas G, Golfinopoulos S, Efthymiadi M, Poulianiti C, Polyzou Konsta MA, Liakopoulos V, Stefanidis I. Routes of Albumin Overload Toxicity in Renal Tubular Epithelial Cells. Int J Mol Sci 2023; 24:9640. [PMID: 37298591 PMCID: PMC10253691 DOI: 10.3390/ijms24119640] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/12/2023] Open
Abstract
Besides being a marker of kidney disease severity, albuminuria exerts a toxic effect on renal proximal tubular epithelial cells (RPTECs). We evaluated whether an unfolded protein response (UPR) or DNA damage response (DDR) is elicited in RPTECs exposed to high albumin concentration. The deleterious outcomes of the above pathways, apoptosis, senescence, or epithelial-to-mesenchymal transition (EMT) were evaluated. Albumin caused reactive oxygen species (ROS) overproduction and protein modification, and a UPR assessed the level of crucial molecules involved in this pathway. ROS also induced a DDR evaluated by critical molecules involved in this pathway. Apoptosis ensued through the extrinsic pathway. Senescence also occurred, and the RPTECs acquired a senescence-associated secretory phenotype since they overproduced IL-1β and TGF-β1. The latter may contribute to the observed EMT. Agents against endoplasmic reticulum stress (ERS) only partially alleviated the above changes, while the inhibition of ROS upregulation prevented both UPR and DDR and all the subsequent harmful effects. Briefly, albumin overload causes cellular apoptosis, senescence, and EMT in RPTECs by triggering UPR and DDR. Promising anti-ERS factors are beneficial but cannot eliminate the albumin-induced deleterious effects because DDR also occurs. Factors that suppress ROS overproduction may be more effective since they could halt UPR and DDR.
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27
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Wu Q, Yan R, Yang H, Wang Y, Zhang C, Zhang J, Cui Z, Wang Y, Sun W. Qing-Re-Xiao-Zheng-Yi-Qi formula relieves kidney damage and activates mitophagy in diabetic kidney disease. Front Pharmacol 2022; 13:992597. [PMID: 36605399 PMCID: PMC9807870 DOI: 10.3389/fphar.2022.992597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Introduction: Qing-Re-Xiao-Zheng-Yi-Qi Formula is an effective prescription in diabetic kidney disease treatment, we have confirmed the efficacy of Qing-Re-Xiao-Zheng therapy in diabetic kidney disease through clinical trials. In this study, we investigated the mechanisms of Qing-Re-Xiao-Zheng-Yi-Qi Formula in the treatment of diabetic kidney disease. Methods: We used Vanquish UHPLCTM to analyze the chemical profiling of Qing-Re-Xiao-Zheng-Yi-Qi Formula freeze-dried powder. We constructed diabetic kidney disease rat models induced by unilateral nephrectomy and high-dose streptozocin injection. We examined blood urea nitrogen, serum creatinine, serum glucose, total cholesterol, triglyceride, serum total protein, albumin, alanine aminotransferase, aspartate aminotransferase and 24 h urinary total protein in diabetic kidney disease rats. The renal pathological changes were observed by HE, Masson, PAS stanning and transmission electron microscopy. The levels of fibrosis-related proteins and mitophagy-related proteins were detected by western blot analysis. We also conducted an immunofluorescence co-localization analysis on podocytes to further investigate the effect of Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment on mitophagy. Results: A total of 27 constituents in Qing-Re-Xiao-Zheng-Yi-Qi Formula were tentatively identified. We found PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could raise body weight and reduce renal index, reduce proteinuria, improve glycolipid metabolic disorders, ameliorate renal fibrosis, and reduce the expression of Col Ⅳ and TGF-β1 in diabetic kidney disease rats. Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could also increase the expression of nephrin, activate mitophagy and protect podocytes in diabetic kidney disease rats and high glucose cultured podocytes. Conclusion: PINK1/Parkin-mediated mitophagy was inhibited in diabetic kidney disease, and Qing-Re-Xiao-Zheng-Yi-Qi Formula treatment could not only ameliorate pathological damage, but also promote mitophagy to protect podocytes in diabetic kidney disease.
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Affiliation(s)
- Qiaoru Wu
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Runze Yan
- Department of Nephrology, Beijing Dongcheng First People’s Hospital, Beijing, BJ, China
| | - Hanwen Yang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Yixuan Wang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Chao Zhang
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Jiale Zhang
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Zhaoli Cui
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China
| | - Yaoxian Wang
- Beijing University of Chinese Medicine, Beijing, BJ, China,*Correspondence: Yaoxian Wang, ; Weiwei Sun,
| | - Weiwei Sun
- Department of Nephrology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, BJ, China,*Correspondence: Yaoxian Wang, ; Weiwei Sun,
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Eleftheriadis T, Pissas G, Filippidis G, Efthymiadi M, Liakopoulos V, Stefanidis I. Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells. Int J Mol Sci 2022; 23:16107. [PMID: 36555751 PMCID: PMC9781434 DOI: 10.3390/ijms232416107] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/21/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium-glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1β, IL-8, and TGF-β1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.
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Zhu Y, Dai L, Yu X, Chen X, Li Z, Sun Y, Liang Y, Wu B, Wang Q, Wang X. Circulating expression and clinical significance of LncRNA ANRIL in diabetic kidney disease. Mol Biol Rep 2022; 49:10521-10529. [PMID: 36129598 PMCID: PMC9618511 DOI: 10.1007/s11033-022-07843-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 08/04/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Long noncoding RNA ANRIL has been found to be involved in the pathogenesis of diabetic kidney disease (DKD) and is expected to be a new target for prevention of DKD. However, the circulating expression and clinical significance of ANRIL in DKD patients is uncertain. This study aims to explore this issue. METHODS The study consisted of 20 healthy controls, 22 T2DM patients (normalbuminuria) and 66 DKD patients (grouped as follows: microalbuminuria, n = 23; macroalbuminuria, n = 22 and renal dysfunction, n = 21). The expressions of ANRIL in peripheral whole blood of all participants were measured by RT-qPCR. RESULTS The expression of ANRIL was significantly up-regulated in DKD patients (microalbuminuria, macroalbuminuria and renal dysfunction groups) than that in healthy control group. ANRIL was also over-expressed in macroalbuminuria and renal dysfunction groups in comparison with normalbuminuria group. ANRIL expression was positively correlated with Scr, BUN, CysC, urine β2-MG and urine α1-MG; while negatively correlated with eGFR in DKD patients. In addition, ANRIL was the risk factor for DKD with OR value of 1.681. The AUC of ANRIL in identifying DKD was 0.922, and the sensitivity and specificity of DKD diagnosis were 83.3% and 90.5%, respectively. CONCLUSION Our results indicated that highly expressed ANRIL in peripheral blood is associated with progression of DKD. Circulating ANRIL is an independent risk factor of DKD and has a highly predictive value in identifying DKD.
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Affiliation(s)
- Yanting Zhu
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Lixia Dai
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Xiangyou Yu
- Department of Endocrinology, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, People's Republic of China
| | - Xintian Chen
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Zhenjiang Li
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Yan Sun
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Yan Liang
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Bing Wu
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Qiong Wang
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China
| | - Xiaoming Wang
- Center of Nephropathy and Hemodialysis, Shaanxi Provincial People's Hospital, 710068, Xi'an, Shaanxi, P.R. China.
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Cheng Y, Wu X, Xia Y, Liu W, Wang P. The role of lncRNAs in regulation of DKD and diabetes-related cancer. Front Oncol 2022; 12:1035487. [PMID: 36313695 PMCID: PMC9606714 DOI: 10.3389/fonc.2022.1035487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 09/19/2022] [Indexed: 11/23/2022] Open
Abstract
Diabetes mellitus often results in several complications, such as diabetic kidney disease (DKD) and end-stage renal diseases (ESRDs). Cancer patients often have the dysregulated glucose metabolism. Abnormal glucose metabolism can enhance the tumor malignant progression. Recently, lncRNAs have been reported to regulate the key proteins and signaling pathways in DKD development and progression and in cancer patients with diabetes. In this review article, we elaborate the evidence to support the function of lncRNAs in development of DKD and diabetes-associated cancer. Moreover, we envisage that lncRNAs could be diagnosis and prognosis biomarkers for DKD and cancer patients with diabetes. Furthermore, we delineated that targeting lncRNAs might be an alternative approach for treating DKD and cancer with dysregulated glucose metabolism.
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Affiliation(s)
- Yawei Cheng
- Department of Disease Prevention, Hainan Province Hospital of Traditional Chinese Medicine, Haikou, China
- Hainan Clinical Research Center for Preventive Treatment of Diseases, Haikou, China
- *Correspondence: Yawei Cheng, ; Peter Wang,
| | - Xiaowen Wu
- Department of Disease Prevention, Hainan Province Hospital of Traditional Chinese Medicine, Haikou, China
| | - Yujie Xia
- Department of Food Science and Technology Centers, National University of Singapore (Suzhou) Research Institute, Suzhou, China
| | - Wenjun Liu
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, China
| | - Peter Wang
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, China
- *Correspondence: Yawei Cheng, ; Peter Wang,
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KITLG Promotes Glomerular Endothelial Cell Injury in Diabetic Nephropathy by an Autocrine Effect. Int J Mol Sci 2022; 23:ijms231911723. [PMID: 36233032 PMCID: PMC9569900 DOI: 10.3390/ijms231911723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/29/2022] [Accepted: 09/29/2022] [Indexed: 11/18/2022] Open
Abstract
Diabetic nephropathy (DN) is an increasing threat to human health. The impact of hyperglycemia or its metabolites, advanced glycation end-products (AGEs), on glomerular endothelial cells (GECs) and their pathophysiologic mechanisms are not well explored. Our results reveal that AGEs increased the expression and secretion of the KIT ligand (KITLG) in GECs. Both AGEs and KITLG promoted endothelial-to-mesenchymal transition (EndoMT) in GECs and further increased the permeability of GECs through the AKT/extracellular-signal-regulated kinase pathway. Inhibition of KITLG’s effects by imatinib prevented AGE-medicated EndoMT in GECs, supporting the belief that KITLG is a critical factor for GEC injury. We found higher KITLG levels in the GECs and urine of db/db mice compared with db/m mice, and urinary KITLG levels were positively correlated with the urinary albumin-to-creatinine ratio (ACR). Furthermore, type 2 diabetic patients had higher urinary KITLG levels than normal individuals, as well as urinary KITLG levels that were positively correlated with urinary ACR and negatively correlated with the estimated glomerular filtration rate. KITLG plays a pathogenic role in GEC injury in DN and might act as a biomarker of DN progression.
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Tanemoto F, Nangaku M, Mimura I. Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition. Front Mol Biosci 2022; 9:1003227. [PMID: 36213117 PMCID: PMC9532834 DOI: 10.3389/fmolb.2022.1003227] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
Epigenetic memory, which refers to the ability of cells to retain and transmit epigenetic marks to their daughter cells, maintains unique gene expression patterns. Establishing programmed epigenetic memory at each stage of development is required for cell differentiation. Moreover, accumulating evidence shows that epigenetic memory acquired in response to environmental stimuli may be associated with diverse diseases. In the field of kidney diseases, the “memory” of acute kidney injury (AKI) leads to progression to chronic kidney disease (CKD); epidemiological studies show that patients who recover from AKI are at high risk of developing CKD. The underlying pathological processes include nephron loss, maladaptive epithelial repair, inflammation, and endothelial injury with vascular rarefaction. Further, epigenetic alterations may contribute as well to the pathophysiology of this AKI-to-CKD transition. Epigenetic changes induced by AKI, which can be recorded in cells, exert long-term effects as epigenetic memory. Considering the latest findings on the molecular basis of epigenetic memory and the pathophysiology of AKI-to-CKD transition, we propose here that epigenetic memory contributing to AKI-to-CKD transition can be classified according to the presence or absence of persistent changes in the associated regulation of gene expression, which we designate “driving” memory and “priming” memory, respectively. “Driving” memory, which persistently alters the regulation of gene expression, may contribute to disease progression by activating fibrogenic genes or inhibiting renoprotective genes. This process may be involved in generating the proinflammatory and profibrotic phenotypes of maladaptively repaired tubular cells after kidney injury. “Priming” memory is stored in seemingly successfully repaired tubular cells in the absence of detectable persistent phenotypic changes, which may enhance a subsequent transcriptional response to the second stimulus. This type of memory may contribute to AKI-to-CKD transition through the cumulative effects of enhanced expression of profibrotic genes required for wound repair after recurrent AKI. Further understanding of epigenetic memory will identify therapeutic targets of future epigenetic intervention to prevent AKI-to-CKD transition.
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Luo Y, Deng D, Lin L, Zhou Y, Wang L, Zou X, Wang X. FGF2 isoforms play distinct roles in tubular epithelial-to-mesenchymal transition in diabetic nephropathy. Exp Cell Res 2022; 420:113355. [PMID: 36115414 DOI: 10.1016/j.yexcr.2022.113355] [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: 03/17/2022] [Revised: 08/17/2022] [Accepted: 09/09/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The role of different isoforms of Fibroblast growth factor-2 (FGF2) in tubular epithelial-to-mesenchymal transition (EMT) in diabetic nephropathy remains unknown. We aimed to evaluate the role of FGF2 isoforms in the pathogenesis of EMT. MATERIALS AND METHODS Western blot and immunofluorescence were used to assess the expression of FGF2 isoforms in db/db mice and high glucose-stimulated HK2 cells. The effects of specific FGF2 isoforms on EMT were explored via overexpression or knockdown of the corresponding isoform in HK2 cells cultivated in high glucose. RESULTS Expression of low molecular weight (LMW) FGF2 was up-regulated while high molecular weight (HMW) FGF2 was down-regulated in the kidney of db/db mice and HK2 cells cultured in high glucose that underwent EMT. Overexpression of the LMW FGF2 enhanced EMT changes, while overexpression of the HMW FGF2 attenuated EMT. Knockdown of HMW FGF2 in HK2 cells promoted the EMT process. CONCLUSIONS The expression and function of LMW and HMW FGF2 differed in the process of EMT in tubular cells. LMW FGF2 contributed to EMT, while HMW FGF2 played a protective role in the EMT process.
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Affiliation(s)
- Yingying Luo
- School of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, 430060, China
| | - Danfang Deng
- Department of Nephrology, Hubei Provincial Hospital of Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China; Department of Nephrology, Hubei Provincial Traditional Chinese Medicine Research Institute, Wuhan, 430074, China; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, 430074, China
| | - Lamei Lin
- Department of Nephrology, Hubei Provincial Hospital of Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China; Department of Nephrology, Hubei Provincial Traditional Chinese Medicine Research Institute, Wuhan, 430074, China; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, 430074, China
| | - Yikun Zhou
- School of Clinical Medicine, Hubei University of Chinese Medicine, Wuhan, 430060, China
| | - Lan Wang
- Department of Nephrology, Hubei Provincial Hospital of Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China; Department of Nephrology, Hubei Provincial Traditional Chinese Medicine Research Institute, Wuhan, 430074, China; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, 430074, China
| | - Xinrong Zou
- Department of Nephrology, Hubei Provincial Hospital of Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China; Department of Nephrology, Hubei Provincial Traditional Chinese Medicine Research Institute, Wuhan, 430074, China; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, 430074, China
| | - Xiaoqin Wang
- Department of Nephrology, Hubei Provincial Hospital of Chinese Medicine, The Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China; Department of Nephrology, Hubei Provincial Traditional Chinese Medicine Research Institute, Wuhan, 430074, China; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, 430074, China.
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Wang X, Liu XQ, Jiang L, Huang YB, Zeng HX, Zhu QJ, Qi XM, Wu YG. Paeoniflorin directly binds to TNFR1 to regulate podocyte necroptosis in diabetic kidney disease. Front Pharmacol 2022; 13:966645. [PMID: 36147345 PMCID: PMC9486100 DOI: 10.3389/fphar.2022.966645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Necroptosis was elevated in both tubulointerstitial and glomerular renal tissue in patients with diabetic kidney disease (DKD), and was most pronounced on glomerulus in the stage with macroalbuminuria. This study further explored whether paeoniflorin (PF) could affect podocyte necroptosis to protect kidney injure in vivo and in vitro. Our study firstly verified that there are obvious necroptosis-related changes in the glomeruli of DKD through bioinformatics analysis combined with clinicopathological data. STZ-induced mouse diabetes model and high-glucose induced podocyte injury model were used to evaluate the renoprotection, podocyte injury protection and necroptosis regulation of PF in DKD. Subsequently, the target protein-TNFR1 that PF acted on podocytes was found by computer target prediction, and then molecular docking and Surface plasmon resonance (SPR) experiments were performed to verify that PF had the ability to directly bind to TNFR1 protein. Finally, knockdown of TNFR1 on podocytes in vitro verified that PF mainly regulated the programmed necrosis of podocytes induced by high glucose through TNFR1. In conclusion, PF can directly bind and promote the degradation of TNFR1 in podocytes and then regulate the RIPK1/RIPK3 signaling pathway to affect necroptosis, thus preventing podocyte injury in DKD. Thus, TNFR1 may be used as a new potential target to treat DKD.
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Affiliation(s)
- Xian Wang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xue-qi Liu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ling Jiang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yue-bo Huang
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Han-xu Zeng
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qi-jin Zhu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiang-ming Qi
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Xiang-ming Qi, ; Yong-gui Wu,
| | - Yong-gui Wu
- Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Center for Scientific Research of Anhui Medical University, Hefei, China
- *Correspondence: Xiang-ming Qi, ; Yong-gui Wu,
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