Angiotensin receptor blocker ameliorates the development of tubulointerstitial injury and fibrosis associated with tubular proteinuria observed in subclinical diabetic kidney disease.

INTRODUCTION

Subclinical Diabetic Kidney Disease (subDKD) is a clinically silent stage of kidney disease secondary to diabetes mellitus (DM), being a public health problem worldwide. The pathogenic mechanism involves hyperglycemia-induced tubulointerstitial injury associated with dysfunction of tubular protein reabsorption and proteinuria, even without any clinical signs like impaired glomerular function. Interestingly, angiotensin receptor blockers (ARBs), known as type 1 angiotensin II receptor (AT1R) antagonists, are effective against proteinuria in many kidney diseases, suggesting the potential involvement of the Renin-Angiotensin System. Herein, we studied the potential renoprotective effects of ARB on the pathogenesis of subDKD.

METHODS

For that, we developed streptozotocin (STZ)-induced type 1 DM [with normal levels of glomerular flow rate] in male Wistar rats, which were daily treated with 30 mg/kg/day losartan, a well-known ARB, via gavage for 6 consecutive weeks starting after induction of diabetes. Four experimental groups were generated: 1) CONT, normoglycemic rat; 2) ARB, normoglycemic rat treated with losartan; 3) subDKD, diabetic rat; 4) subDKD+ARB, diabetic rat treated with losartan.

RESULTS

Comparing with the CONT group, the subDKD group presented: 1) impaired tubular reabsorption of Na+ and Cl-; 2) proteinuria associated with dysfunction in cortical albumin endocytosis; 3) increased levels of urinary lactate dehydrogenase and γ-glutamyltransferase, markers of kidney and proximal tubule epithelial cell injuries, respectively; 4) increased kidney injury score and tubulointerstitial injury; 5) increased cortical type 1 collagen deposition. Interestingly, the ARB treatment ameliorated all parameters observed in diabetic rats (subDKD+ARB group). No significant changes were observed in the ARB group.

DISCUSSION: Altogether, our findings indicated that ARB promotes renoprotective effects by attenuating AT1R-associated tubular damage and proteinuria of tubular origin observed in subDKD.