Candesartan differentially regulates distal sodium transporters and channel subunits in cortex versus medulla in streptozotocin‐induced diabetic rats.

Abstract

Diabetes is associated with increased activity of the renal renin angiotensin system (RAS). Previously, we demonstrated that streptozotocin (STZ)-induced diabetic rats have significantly increased abundances of renal distal sodium transporters and channels, e.g., the thiazide-sensitive Na-Cl cotransporter (NCC) and the epithelial sodium channel (ENaC). To determine the role of elevated RAS activity in these changes, male Sprague-Dawley rats (100–150 g) were made diabetic by intravenous injection of STZ (65 mg/kg·bw) or treated with vehicle (n = 12/group). Rats were fed standard 1% NaCl rodent chow and watered ad libitum. After 14 days, rats were further divided (n = 6/group) to receive candesartan in the drinking water (2 mg/kg/day) or plain water for 7 additional days. Immunoblotting revealed, in cortex, diabetes caused a modest increase in NCC, β- and γ-ENaC (85-kDa band) abundances (band density ~ 150% of non-diabetic controls). Candesartan not only reversed these increases, but significantly reduced abundance of NCC and ENaC subunits to ~50% of non-candesartan-treated rats in both diabetic and non-diabetic rats. In contrast, in the medulla, diabetes caused a much greater increase in ENaC subunits and α-1-Na-K-ATPase (band densities 200–600% of non-diabetic controls) and these increases were irreversible by candesartan. Moreover, candesartan increased β- and γ-ENaC in the non-diabetic rats, in the medulla tip. Thus the increased abundances of sodium transporters in the cortex, but not the medulla, with diabetes, are candesartan-sensitive, and therefore, likely due to enhanced AT1-mediated signaling.