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The Angiotensin II Type 1 Receptor Mediates Renal Interstitial Content of Tumor Necrosis Factor- in Diabetic Rats

The Department of Medicine (H.M.S., A.A., P.A.), University of Virginia School of Medicine, Charlottesville, Virginia 22904; and Novartis Pharmaceuticals Corporation (R.W.), East Hanover, New Jersey 07936

Address all correspondence and requests for reprints to: Helmy M. Siragy, M.D., Box 801409, Department of Medicine, University of Virginia Health Sciences Center, 450 Ray C. Hunt Drive, Charlottesville, Virginia 22908. E-mail: hms7a{at}virginia.edu.

A unique microdialysis technique was used to demonstrate that increased levels of angiotensin II (Ang II) and consequent stimulation of the Ang II type 1 (AT₁) receptor increase the renal content of TNF- in diabetes. Recovery of Ang II and TNF- in renal interstitial fluid (RIF) was measured in conscious rats before and weekly for 12 wk after induction of diabetes with streptozocin and in response to oral valsartan (10 mg/kg·d). Recovery of Ang II in RIF was significantly higher in diabetic rats than in nondiabetic rats. In diabetic rats, RIF recovery of TNF- increased by approximately 67% over baseline, whereas it was unchanged in nondiabetic rats. AT₁ receptor blockade with valsartan prevented the increase in TNF- in the diabetic group. This study shows that diabetes is associated with an increase in the vasoconstrictive hormone Ang II and the inflammatory cytokine TNF-, both of which play a role in accelerating renal function decline in diabetic nephropathy. The study also confirms that valsartan reduces intrarenal level of TNF- by acting on Ang II at the AT₁ receptor level. This finding of a potential antiinflammatory effect for valsartan is new and in addition to its known antihypertensive effects.

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