Abstract
Azilsartan, an angiotensin II receptor blocker, demonstrated anti-hypertensive and organ protective effects in hypertension. We investigated if azilsartan can be utilized in ameliorating kidney damage associated with cardiometabolic syndrome using Zucker Diabetic Fatty (ZDF) rats. Two groups of 6-8 week-old male ZDF rats were treated with vehicle or azilsartan (10 mg/kg/d, p.o.) for 8 weeks. A set of male Zucker Diabetic Lean (ZDL) rats were used as the control group. At the end of the treatment period, urine and plasma samples were collected for biochemical analysis while kidney tissues were collected for histopathological examination (n=6/group). ZDF rats were diabetic with fasting blood glucose levels averaging 287±45 mg/dL compared to 107±6 mg/dL in ZDL rats. Azilsartan treatment ameliorated hyperglycemia in ZDF rats (167±46 mg/dL). ZDF rats were also hypertensive compared to ZDL rats (181±4 vs 126±4 mmHg), and azilsartan treatment attenuated blood pressure in ZDF rats (109±4 mmHg). ZDF rats demonstrated marked renal damage compared to ZDL with elevated urinary excretion of albumin (ZDF vs ZDL, 92±47 vs 4±2 mg/d) and nephrin (842±364 vs 16±4 μg/d). ZDF rats also had 2-4-fold higher tubular cast formation and glomerular injury compared to ZDL rats. In ZDF rats, azilsartan treatment markedly reduced renal injury by attenuating elevated urinary albumin (7±2 mg/d) and nephrin (73±28 ug/d) along with a reduction in renal tubular cast formation and glomerular injury index. ZDF rats demonstrated increased inflammation and oxidative stress with elevated urinary monocyte chemoattaractant protein-1 (MCP-1) excretion (ZDF vs ZDL, 645±373 vs 319±76 ng/d) and kidney malondialdehyde (MDA) content (5±1 vs 10±1 μmol/mg). Azilsartan treatment reduced inflammation and oxidative stress in ZDF rats by reducing MCP-1 (335±80 ng/d) and kidney MDA content (6±1 ug/d). In summary, we demonstrate marked kidney protective, anti-inflammatory, and anti-oxidative effects of azilsartan in cardiometabolic syndrome ZDF rats. Support provided by Takeda Pharmaceuticals Inc., USA
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