Abstract

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions that 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 and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor κB (NFκB), 12-lipooxygenase, cyclooxygenase (COX)-1, COX-2, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (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, 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-fold), activation of NFκB, 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.