The angiotensin II type 1 receptor mediates renal interstitial content of tumor necrosis factor-alpha in diabetic rats.
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 (AT(1)) receptor increase the renal content of TNF-alpha in diabetes. Recovery of Ang II and TNF-alpha 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-alpha increased by approximately 67% over baseline, whereas it was unchanged in nondiabetic rats. AT(1) receptor blockade with valsartan prevented the increase in TNF-alpha 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-alpha, 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-alpha by acting on Ang II at the AT(1) receptor level. This finding of a potential antiinflammatory effect for valsartan is new and in addition to its known antihypertensive effects.
The Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia 22904, USA. hms7a@virginia.edu
Helmy M
HM
Siragy
Alaa
A
Awad
Peter
P
Abadir
Randy
R
Webb
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D017551:Microdialysis / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000652:urine*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D000959:Antihypertensive Agents; D001786:Blood Glucose; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000068756:Valsartan; D014633:Valine