Effects of canagliflozin and irbesartan on renal fibrosis in Dahl salt-sensitive rats

Hypertension is one of the major contributors to cardiovascular and chronic kidney disease (CKD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors and angiotensin receptor blockers (ARBs) have become the preferred treatment for patients with CKD. However, the renoprotective effects of the combined therapy of the two drugs on hypertensive renal fibrosis are still largely understood. The aim of this study was to compare the antifibrotic effects of canagliflozin, with or without irbesartan, in the kidneys of Dahl salt-sensitive (Dahl SS) rats on a high salt (HS) diet. After the preconditioning stage, Dahl SS rats (n = 47) were divided into 5 experimental groups as follows: low salt control (n=7), HS control (n=10), high salt with canagliflozin (n=10), high salt with irbesartan (n=10), and high salt with canagliflozin plus irbesartan (n=10). Mean food and water intake, body weight (BW), and systolic blood pressure (SBP) were measured during the whole experimental period. After 12 weeks, the rats were euthanized, and the kidneys were excised for histomorphometric evaluation and immunohistochemical evaluation. An HS diet increased SBP, renal fibrosis, expression of fibrotic protein factors, and TGF-β/Smad2/3 pathway compared to the LS group. We found that irbesartan reduced SBP and slowed the loss of renal function. Canagliflozin significantly reduced BW and renal fibrosis and downregulated the TGF-β/Smad2/3 pathway. The combined therapy showed better renoprotection in all outcome parameters. In conclusion, these results indicate that canagliflozin and irbesartan exert different benefits on nephroprotection in salt-sensitive hypertensive rats.