Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice.

Linda A Gallo,Volker Vallon,Shang-Ming Yeh,Carol Pollock,Domenica A Mccarthy,Amelia K Fotheringham,Toni L Kinneally,Danielle J Borg,Micheal S Ward,Aowen Zhuang,Ben M Harvie,Usha Panchapakesan,Nicole B Flemming,Josephine M Forbes,Hermann Koepsell

doi:10.1038/srep26428

Abstract

Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.

Highlights

Diabetic nephropathy accounts for 35–40% of new cases of end-stage renal disease in the developed world[1,2]
We aimed to determine whether the administration of an SGLT2 inhibitor, empagliflozin, improves early manifestations of diabetic nephropathy in the db/db mouse model of type 2 diabetes
Db/db and db/m littermates were treated with empagliflozin (10 mg/kg/day) or vehicle by single daily oral gavage for 10 weeks

Summary

Introduction

Diabetic nephropathy accounts for 35–40% of new cases of end-stage renal disease in the developed world[1,2]. Sodium-dependent glucose transporter (SGLT)-2 inhibitors, a new anti-diabetic strategy, target the renal proximal tubules to block glucose reabsorption, thereby enhancing urinary glucose excretion and conferring anti-hyperglycemic effects They are indicated for use in individuals with type 2 diabetes (provided kidney function is at least moderate) and are under clinical investigation as an add-on to exogenous insulin in type 1 diabetes. Blood glucose levels were matched between diabetic groups using insulin (group means >20 mmol/L) and, unlike an angiotensin receptor blocker, empagliflozin did not provide renoprotection These data highlight that, in models of early diabetic nephropathy, renoprotection from hyperglycemia may be afforded only when circulating glucose levels and/or the activity of the RAS are sufficiently decreased. Whether these renal benefits were superior to the first-line, glucose-lowering therapy for type 2 diabetes, metformin, and/or additive upon empagliflozin and metformin dual therapy, were assessed

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