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-α in diabetes. Recovery of Ang II and TNF-α 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-α increased by approximately 67% over baseline, whereas it was unchanged in nondiabetic rats. AT1 receptor blockade with valsartan prevented the increase in TNF-α 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-α, 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-α 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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