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The SGLT2 Inhibitor, Empagliflozin, Attenuates Some Markers of Renal Fibrosis without Improving Albuminuria in Diabetic Db/Db Mice
Author(s) -
Gallo Linda A,
Ward Micheal S,
Fotheringham Amelia K,
Zhuang Aowen,
Koepsell Hermann,
Vallon Volker,
Pollock Carol,
Panchapakesan Usha,
Forbes Josephine M
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.740.18
Subject(s) - empagliflozin , albuminuria , endocrinology , medicine , metformin , diabetic nephropathy , glomerular hyperfiltration , type 2 diabetes , renal glucose reabsorption , kidney , diabetes mellitus , urology
Sodium‐dependent‐glucose‐transporter 2 (SGLT2) inhibitors are a novel therapy for type 2 diabetes. They block glucose reabsorption by the kidney which promotes urinary glucose excretion and lowers blood glucose levels. We aimed to determine whether SGLT2 inhibition is renoprotective in a mouse model of type 2 diabetes and nephropathy. Male db/db and db/m (C57BLKS/J) mice were administered with once‐daily oral treatment of the SGLT2 inhibitor, empagliflozin (10mg/kg/day), or vehicle from 10–20 weeks of age (n=11/group). These were compared with db/db mice which received metformin (250mg/kg/day) or empagliflozin + metformin co‐therapy (dose as per single). At baseline, all db/db mice were obese with hyperglycemia ( P <0.05). Towards the study end, these mice had glomerular hyperfiltration, albuminuria, increased levels of urinary kidney injury molecule‐1 (KIM‐1), increased kidney weight, tubulointerstitial total collagen accumulation, glomerulosclerosis, and increased renal expression of pro‐fibrotic genes ( P <0.05). Treatment with empagliflozin, either as a mono‐ or co‐therapy, improved glycemic control compared to vehicle (glycated hemoglobin 6.6% and 5.7%, respectively, vs 9.6%, P <0.05) but did not reduce albuminuria, urinary KIM‐1, kidney weight, or glomerulosclerosis. Empagliflozin in diabetic mice reduced total collagen accumulation and renal expression of Fn1 and Tgfb1 and, when co‐administered with metformin, also attenuated the increased renal cortical expression of ColIV and Ctgf, and glomerular hyperfiltration ( P <0.05). Empagliflozin, alone or in combination with metformin, increased intra‐renal renin activity compared to vehicle‐treated diabetic mice ( P <0.05) but did not increase cortical angiotensin II content. In this mouse model of diabetic nephropathy, blood glucose lowering with SGLT2 inhibition did not improve albuminuria but attenuated some histological and molecular markers of renal fibrosis. Hyperglycemia and albuminuria‐onset prior to commencement of treatment may have been sufficient for disease development and rendered our study an interventional approach. Thus, early, sufficient, and stable blood glucose lowering with SGLT2 inhibition, possibly in combination with RAS blockade, may be required to achieve maximal renoprotection in diabetes. Further, the potential for SGLT2 inhibition to slow progression to more advanced stages of kidney disease remains to be assessed. Support or Funding Information National Health and Medical Council of Australia and Heart Foundation (Australia). Boehringer‐Ingelheim (Germany) provided the empagliflozin.