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Article

SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes

1
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
2
Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (IC&G SB RAS), Lavrentjev Prospect 10, 630090 Novosibirsk, Russia
3
Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2987; https://doi.org/10.3390/ijms21082987
Received: 12 April 2020 / Revised: 19 April 2020 / Accepted: 21 April 2020 / Published: 23 April 2020
(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)
Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male db/db mice were randomly assigned to treatment with empagliflozin, linagliptin, empagliflozin–linagliptin or vehicle for 8 weeks. Age-matched non-diabetic db/+ mice acted as controls. To estimate glomerular autophagy, immunohistochemistry for beclin-1 and LAMP-1 was performed. Podocyte autophagy was assessed by counting the volume density (Vv) of autophagosomes, lysosomes and autolysosomes by transmission electron microscopy. LC3B and LAMP-1, autophagy markers, and caspase-3 and Bcl-2, apoptotic markers, were evaluated in renal cortex by western blot. Vehicle-treated db/db mice had weak glomerular staining for beclin-1 and LAMP-1 and reduced Vv of autophagosomes, autolysosomes and lysosomes in podocytes. Empagliflozin and linagliptin, both as monotherapy and in combination, enhanced the areas of glomerular staining for beclin-1 and LAMP-1 and increased Vv of autophagosomes and autolysosomes in podocytes. Renal LC3B and Bcl-2 were restored in actively treated animals. LAMP-1 expression was enhanced in the empagliflozin group; caspase-3 expression decreased in the empagliflozin–linagliptin group only. Mesangial expansion, podocyte foot process effacement and urinary albumin excretion were mitigated by both agents. The data provide further explanation for the mechanism of the renoprotective effect of SGLT2 inhibitors and DPP4 inhibitors in diabetes. View Full-Text
Keywords: autophagy; podocyte; type 2 diabetes; diabetic nephropathy; empagliflozin; linagliptin autophagy; podocyte; type 2 diabetes; diabetic nephropathy; empagliflozin; linagliptin
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MDPI and ACS Style

Korbut, A.I.; Taskaeva, I.S.; Bgatova, N.P.; Muraleva, N.A.; Orlov, N.B.; Dashkin, M.V.; Khotskina, A.S.; Zavyalov, E.L.; Konenkov, V.I.; Klein, T.; Klimontov, V.V. SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes. Int. J. Mol. Sci. 2020, 21, 2987. https://doi.org/10.3390/ijms21082987

AMA Style

Korbut AI, Taskaeva IS, Bgatova NP, Muraleva NA, Orlov NB, Dashkin MV, Khotskina AS, Zavyalov EL, Konenkov VI, Klein T, Klimontov VV. SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes. International Journal of Molecular Sciences. 2020; 21(8):2987. https://doi.org/10.3390/ijms21082987

Chicago/Turabian Style

Korbut, Anton I., Iuliia S. Taskaeva, Nataliya P. Bgatova, Natalia A. Muraleva, Nikolai B. Orlov, Maksim V. Dashkin, Anna S. Khotskina, Evgenii L. Zavyalov, Vladimir I. Konenkov, Thomas Klein, and Vadim V. Klimontov 2020. "SGLT2 Inhibitor Empagliflozin and DPP4 Inhibitor Linagliptin Reactivate Glomerular Autophagy in db/db Mice, a Model of Type 2 Diabetes" International Journal of Molecular Sciences 21, no. 8: 2987. https://doi.org/10.3390/ijms21082987

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