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©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice
Vadim V Klimontov, Anton I Korbut, Iuliia S Taskaeva, Nataliya P Bgatova, Maksim V Dashkin, Nikolai B Orlov, Anna S Khotskina, Evgenii L Zavyalov, Thomas Klein
Vadim V Klimontov, Anton I Korbut, Maksim V Dashkin, Laboratory of Endocrinology, 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), Novosibirsk 630060, Russia
Iuliia S Taskaeva, Nataliya P Bgatova, Laboratory of Ultrastructural Research, 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), Novosibirsk 630060, Russia
Nikolai B Orlov, Laboratory of Clinical Immunogenetics, 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), Novosibirsk 630060, Russia
Anna S Khotskina, Evgenii L Zavyalov, Center for Genetic Resources of Laboratory Animals, Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia
Thomas Klein, Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH, Biberach 88397, Germany
Author contributions: Klimontov VV designed and coordinated the study; Korbut AI, Taskaeva IS, Dashkin MV, Orlov NB and Khotskina AS performed the experiments, acquired and analyzed data; Klimontov VV, Bgatova NP, Zavjalov EL and Klein T interpreted the data; Klimontov VV and Korbut AI wrote the manuscript; all authors approved the final version of the article.
Supported by Ministry of Science and Higher Education of Russia (the budget projects No. 0324-2019-0045/0324-2019-0045-C-02; grant No. RFMEFI62119X0023) and Boehringer Ingelheim Pharma.
Institutional review board statement: The protocol was approved by the Ethics Committee of the Institute of Clinical and Experimental Lymphology (Protocol 1/2; 1 April 2014) and by the Inter-Institutional Animal Ethics Committee based on the Institute of Cytology and Genetics SB RAS (Protocol 21; 1 April 2014).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Center of Genetic Resources of Laboratory Animals based on the SPF Vivarium of Institute of Cytology and Genetics SB RAS (Protocol 24; 8 April 2014).
Conflict-of-interest statement: VVK received honorariafrom Boehringer Ingelheim for the lectures and advising boards. TK is an employee of Boehringer Ingelheim Pharma. Other authors declare they have no competing interest.
Data sharing statement: The datasets used and analyzed during the current study are available from the corresponding author on the request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Vadim V Klimontov, DSc, MD, PhD, Professor, Laboratory of Endocrinology, 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), 2 Timakov Street, Novosibirsk 630060, Russia. klimontov@mail.ru
Received: July 14, 2020
Peer-review started: July 14, 2020
First decision: September 21, 2020
Revised: September 28, 2020
Accepted: October 13, 2020
Article in press: November 9, 2020
Published online: December 15, 2020
BACKGROUND
Modern guidelines recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease. However, the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.
AIM
To estimate the effect of the SGLT2 inhibitor, empagliflozin (EMPA), on the structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice.
METHODS
We treated 8-wk-old male db/db mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. Age-matched male db/+ mice were included as non-diabetic controls. Parameters of body composition, glycemic and lipid control, and plasma concentrations of leptin, insulin and glucagon were assessed. We evaluated renal hypertrophy as kidney weight adjusted to lean mass, renal function as plasma levels of creatinine, and albuminuria as the urinary albumin-to-creatinine ratio (UACR). Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure, respectively. Glomerular nephrin and transforming growth factor beta (TGF-β) were assessed by immunohistochemistry.
RESULTS
Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment; increased plasma concentrations of fructosamine, glycated albumin, cholesterol, leptin, and insulin, and elevated UACR were detected. Mesangial expansion, glomerular basement membrane thickening, and increased area of TGF-β staining in glomeruli were revealed in vehicle-treated mice. Podocytopathy was manifested by effacement of foot processes; nephrin-positive areas in glomeruli were reduced. EMPA decreased the levels of glucose, fructosamine and glycated albumin, UACR, kidney hypertrophy, mesangial expansion, glomerular basement membrane thickening, and glomerular TGF-β staining, alleviated podocytopathy and restored glomerular staining of nephrin.
CONCLUSION
These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease. The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.
Core Tip: In the present study, we assessed the influence of the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin (EMPA) on glomerular structure, with a focus on podocytes, and glomerular staining of nephrin in db/db mice, a model of type 2 diabetic nephropathy. We treated 8-wk-old mice with EMPA (10 mg/kg/d) or vehicle for 8 wk. The results demonstrated that EMPA attenuates podocytopathy and enhances glomerular nephrin staining. These effects were accompanied by mitigation of renal hypertrophy and glomerular transforming growth factor beta expression and a decrease in albuminuria. These results contribute to the understanding of the renal protective effect of SGLT2 inhibitors in diabetes.
