Candesartan restored the altered renal insulin receptor protein and cytokine profile, and reduces nephropathy in the obese Zucker rat despite its propensity to worsen diabetes

Abstract

Candesartan (CAN), an angiotensin type 1 receptor (AT1R) antagonist, exhibit renoprotective effect in obese Zucker rats (OZ). We have reported downregulated renal insulin receptor (IR) in hyperinsulinemic OZ. IR could attenuate inflammation via NO production. Cytokines are central to the pathology of nephropathy. To determine the effect of chronic CAN therapy on cytokine expression and their correlation with IR in OZ kidney, male lean (LZ) and obese (OZ) Zucker rats were treated without or with CAN (25 mg CAN/kg·diet) (n= 6/treatment/body type) for 12 weeks. Histochemical staining revealed attenuated nephropathy by CAN in OZ. CAN significantly reduced urinary albumin and plasma creatinine levels in OZ. Surprisingly, glucose tolerance was worsened in CAN‐treated OZ. ELISA‐based cytokine array in the whole kidney revealed that OZ had a marked increase expression of monocyte chemoattractant protein‐1 (MCP‐1, 202 ± 58 vs. 68 ± 6 pg/ml) and interleukin (IL‐1 β, 235 ± 30 vs. 152 ± 11 pg/ml) relative to LZ. CAN treatment restored these levels to LZ levels. Furthermore, IL‐10, a cytokine important for inhibiting the synthesis of pro‐inflammatory cytokines, was significantly lower in OZ (135 ± 9 vs. 250 ± 9 pg/ml) and CAN treatment restored its level to LZ. Surprisingly, other proinflammatory cytokines including IL‐1α and IL‐6 were significantly below LZ level in OZ and were restored to lean levels by CAN. In addition, renal IR protein levels positively correlated with IL‐10 and negatively with IL‐1 β (p=0.02). These data demonstrate that blockade of AT1R reduces MCP‐1 and IL‐1 β and upregulate IL‐10. The correlation of IR with inflammatory responses suggests either inflammation reduced IR or IR action is important in preventing inflammation. Additional studies are required. NKF (ST) and NIH (CE)