Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction.
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 kappaB (NFkappaB), 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 NFkappaB, 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.
Vaziri
N D
ND
Division of Nephrology and Hypertension, University of California, Irvine, CA, USA. ndvaziri@uci.edu
Bai
Y
Y
Ni
Z
Z
Quiroz
Y
Y
Pandian
R
R
Rodriguez-Iturbe
B
B
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002452:Cell Count; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D007249:Inflammation; D007668:Kidney / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D009392:Nephrectomy; D009929:Organ Size; D018384:Oxidative Stress; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis*; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis; D015854:Up-Regulation
D047228:Angiotensin II Type 1 Receptor Blockers; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011451:Prostaglandin-Endoperoxide Synthases