Regulation of Angiotensin II Type I Receptor (AT1R) Protein Levels in the Obese Zucker Rat Kidney and Urine

Abstract

Increased renal expression of the angiotensin II, type-1 receptor (AT1R) has been associated with increased blood pressure (BP) and progression of renal disease. We tested whether common medications used to treat hypertension and the metabolic syndrome alter renal AT1R; and whether urine AT1R can be used as a reasonable noninvasive marker of renal levels in the obese Zucker rat, a model for human metabolic syndrome. Immunoblotting revealed that renal and urinary levels of AT1R were significantly higher in obese versus lean rats and correlated (R = 0.62, p < 0.05). Chronic treatment with BP lowering, candesartan, an AT1R antagonist, increased renal levels of AT1R in both lean (282% of lean controls) and obese (178% of obese controls) rats, but decreased urine AT1R levels in obese rats (72% of obese controls). Similarly, chronic treatment with rosiglitazone (RGZ), a peroxisome proliferator activated receptor (subtype γ) agonist, significantly decreased urine (43% of obese controls) but not renal AT1R (105%) in obese rats. Blood pressure, measured by radiotelemetry, was significantly correlated in untreated and RGZ-treated rats to renal AT1R (R = 0.57, p = 0.0035). Finally, high- (4%) and medium- (0.4%) NaCl diets increased excretion of AT1R in obese rats to ∼400% of low- (0.04%) NaCl diet. This effect was markedly blunted in lean rats. Overall, we demonstrate increased renal AT1R levels in obese rats. Urine AT1R correlated with renal levels only in the untreated state. Relative salt-sensitivity of AT1R excretion in obese, relative to lean rats, may have implications for both BP and renal disease in the metabolic syndrome.

Keywords:

• RAS
• hypertension
• RAAS
• insulin resistance
• diabetes