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Angiotensin II Type 2 Receptor Agonist C21 Reduces Kidney Damage And Improves Renal Tubular Functions In High Sodium Diet‐Fed Obese Zucker Rats

Salt‐sensitivity has been implicated in chronic kidney damage (CKD) and impairing renal function, particularly in obesity. Earlier we have reported blood‐pressure and oxidative stress reducing effects of angiotensin AT2 receptor (AT2R) agonist C21 in kidney of high sodium diet (HSD)‐fed obese Zucker rat (OZR). Present study tested the effects of C21 on indices of renal function in HSD‐fed OZR. Obese rats were fed normal sodium diet (NSD) or 4% HSD for 14 days, with/without C21 (1 mg/kg/day) delivered subcutaneously via osmotic pump. Compared to NSD controls, HSD rats exhibited severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate (GFR), and an increase in urinary leak and activity of N‐acetyl‐β‐D‐glucosaminidase, a lysosomal enzyme and a marker of tubular damage, which were all improved by C21. C21 treatment reduced protein‐to‐creatinine (uPcr), albumin‐to‐creatinine (uAcr) as well as fractional excretion of protein (FEpro) and albumin (FEalb) in HSD‐fed OZR, which is independent of changes in protein recycling receptors – megalin and cubilin. HSD intake has also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen‐to‐creatinine (UN‐to‐cr) and fractional excretion of urea nitrogen (FEUN), and reduced urine‐to‐plasma creatinine (UPcr), which were modestly, but insignificantly, improved by C21. Collectively, we conclude that AT2R agonist C21 reduced glomerular protein leak and preserved lysosomal function and thus reduced exposure of nephrotic proteins to tubular lumen suggesting a potential role of AT2R in protecting glomerulus and renal tubules during HSD intake in obesity.