ELEVATED SYSTEMIC LEVELS OF ANGIOTENSIN-(1-7) MODULATE RENAL DYSFUNCTION OBSERVED IN THE EARLY STAGE OF DIABETIC KIDNEY DISEASE

Diabetic Kidney Disease (DKD) is a life-threatening complication of diabetes mellitus associated with hyperglycemia-induced tubular albuminuria and modulation of intrarenal Renin-Angiotensin System components. However, the potential role of angiotensin-(1-7) [Ang-(1-7)] is still poorly known. We aimed to study the potential role of Ang-(1-7) in the tubular injury and dysfunction observed in the early DKD. Streptozotocin-induced DKD animal model was used. Eight experimental groups were generated: 1) Sprague Dawley (SD)-ND, normoglycemic rats (control, n=8); 2) SD-D, diabetic rats (n=8); 3) L3292-ND, normoglycemic TGR(A1-7)3292 rats [high systemic Ang-(1-7)] (n=9); 4) L3292-D, diabetic TGR(A1-7)3292 rats (n=9); 5) SD-ND+HPßCD, normoglycemic rats treated with empty hydroxypropyl ß-cyclodextrin (HPßCD) used as vehicle via gavage (n= 5); 6) SD-D+HPßCD, diabetic rats treated with vehicle (n= 10); 7) SD-ND+ HPßCD-A-(1-7), normoglycemic rats daily treated with 30 μg/kg/day Ang-(1-7) included in HPßCD [HPßCD-Ang-(1-7)] via gavage (n= 5); 8) SD-D+ HPßCD-A-(1-7), diabetic rats treated with HPßCD-Ang-(1-7) (n= 11) (CEUA-UFMG n° 300/2024). All the analyses were carried out after 3 weeks after diabetes induction. When compared with normoglycemic groups (SD-ND and SD-ND+HPßCD groups), the diabetic groups (SD-D and SD-D+HPßCD groups) presented increase in: (1) the fractional excretion (FE) of water, K+, Na+, Cl- and glucose; (2) both urinary protein:creatinine ratio (UP:Cr) and in FEproteins associated with drop in cortical albumin-FITC uptake; (3) urinary lactate dehydrogenase and urinary 𝛾-glutamyl transferase (kidney injury markers); (4) cortical tubule-interstitial injury as well as collagen deposition. Interestingly, all these modifications were attenuated in L3292-D and SD-D+ HPßCD-A-(1-7) groups. No significant changes were observed in the L3292-ND and SD-ND+ HPßCD-A-(1-7) groups. Our findings suggest that Ang-(1-7) attenuates the development of tubular injury and dysfunction observed in early DKD.