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312 ROLE OF UP-REGULATION OF AT1 RECEPTOR IN OXIDATIVE STRESS, INFLAMMATION, AND PROGRESSIVE INJURY IN RENAL MASS REDUCTION.
  1. Y. Bai1,
  2. Z. Ni1,
  3. B. Rodriguez-Iturbe1,
  4. N. D. Vaziri1
  1. 1University of California, Irvine, Irvine, CA.

Abstract

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, progressive glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions, which are, in part, caused by local activation of AT1 receptor (AT1r) by angiotensin II (Ang II). In the present study, we explored the effects of renal mass reduction (5/6 nephrectomy) with and without AT1r blockade (losartan, 30 mg/kg/d for 8 weeks) on AT1r and AT2r expressions and pathways involved in oxidative stress and inflammation [NAD(P)H oxidase subunits, NF-κB, 12/15-lipo-oxygenase, COX-1, COX-2, MCP-1, PAI-1, and renal infiltration of T cells and macrophages], as well as renal function and structure. The untreated group exhibited a marked increase (334%) in AT1r (but not AT2r) abundance in the remnant kidney. This was coupled with up-regulations of NAD(P)H oxidase [gp91phox (164%), p22phox (132%), and P47phox (183%) subunits], COX-2 (227%), 12/15-lipo-oxygenase (198%), MCP-1 (269%), and PAI-1 (10-fold), activation of NF-κB, and interstitial infiltration of T cells and macrophages, as well as deterioration of renal function and structure. AT1r blockade prevented or attenuated the associated biochemical and histologic abnormalities and decelerated the rate of deterioration of renal function and structure in this model. Thus, the study demonstrated a link between up-regulation of AT1r and oxidative stress, inflammation, and progression of renal disease in rats with renal mass reduction.

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