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A nonpeptide angiotensin II type 2 receptor agonist prevents renal inflammation in early diabetes

Luis C Matavelli1, Roberto Zatz, Helmy M Siragy

  • 1*Renal Division, Department of Medicine, School of Medicine, University of São Paulo, São Paulo, Brazil; and †Department of Medicine, University of Virginia Health System, Charlottesville, VA.

Journal of Cardiovascular Pharmacology
|January 16, 2015
PubMed

Insights

Direct stimulation of angiotensin II type 2 receptors (AT2R) with Compound 21 reduced albuminuria in diabetic rats by decreasing inflammation and oxidative stress, improving nitric oxide (NO) and cGMP levels.

Area of Science:

  • Nephrology
  • Endocrinology
  • Pharmacology

Background:

  • Diabetic kidney disease is characterized by albuminuria, inflammation, and oxidative stress.
  • The role of angiotensin II type 2 receptors (AT2R) in mitigating these diabetic complications is not fully understood.

Purpose of the Study:

  • To investigate the therapeutic potential of direct AT2R stimulation using Compound 21 (C21) in a rat model of diabetes.
  • To determine if C21 treatment can ameliorate albuminuria, renal inflammation, and oxidative stress in diabetic rats.

Main Methods:

  • Streptozotocin-induced diabetic (DM) and normoglycemic control (NC) rats were treated with vehicle or C21 for 4 weeks.
  • Evaluated blood pressure, urinary albumin to creatinine ratio (UACR), and renal interstitial fluid (RIF) markers including TNF-α, IL-6, NO, cGMP, and 8-isoprostane.
  • Assessed renal mRNA expression of TNF-α, IL-6, and AT2R.

Main Results:

  • DM rats exhibited increased UACR, RIF TNF-α, IL-6, 8-isoprostane, and inflammatory gene expression, alongside reduced RIF NO and cGMP.
  • C21 treatment in DM rats significantly limited UACR elevation, normalized inflammatory markers and oxidative stress, and enhanced NO and cGMP production.
  • C21 did not affect these parameters in normoglycemic rats, and AT2R expression increased in DM rats but was not altered by C21.

Conclusions:

  • Direct AT2R stimulation with C21 effectively improves diabetic albuminuria.
  • AT2R activation mitigates renal inflammation and oxidative stress in diabetes.
  • Enhanced nitric oxide and cGMP production contribute to the renoprotective effects of AT2R stimulation in diabetic conditions.

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