Received for publication April 5, 2007.
Revised July 13, 2007.
Accepted for publication July 13, 2007.

Intra-renal angiotensin II/AT₁ Receptor, Oxidative Stress, Inflammation and Progressive Injury in Renal Mass Reduction

Abstract

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulo-interstitial injury and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative and inflammatory reactions which are, in part, driven by local AT₁ receptor (AT₁r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT₁r blockade (losartan for 8 weeks) on AT₁r and AT₂r, Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, NF_kB, 12-lipooxygenase, COX-1, COX-2, MCP-1, PAI-1, renal T cell and macrophage infiltration] as well as renal function and structure. The untreated group exhibited hypertension, deterioration of renal function and structure, reduced or unchanged plasma renin activity and aldosterone concentration, marked up-regulations of AT₁r (250%), Ang II-expressing cell count (>20 fold), NAD(P)H oxidase subunits (gp91^phox , p22^phox, and P47^phox; 20%-40%), COX-2 (250%), 12- lipooxygenase (100%), MCP-1 (400%), and PAI-1 (>20 folds), activation of NF_kB, and interstitial infiltrations of T-cells and macrophages in the remnant kidneys. AT₁r blockade attenuated the biochemical and histological abnormalities, prevented hypertension and decelerated deterioration of renal function and structure. Thus the study demonstrated a link between up-regulation of Ang II/AT₁r system and oxidative stress, inflammation, hypertension and progression of renal disease in rats with renal mass reduction.

Key words: COX-1, COX-2, ESRD, chronic kidney disease, hypertension, lipooxygenase

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