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, 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 AT 1 receptor (AT 1 r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT 1 r blockade (losartan for 8 weeks) on AT 1 r and AT 2 r and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor B (NFB), 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 AT 1 r (250%), Ang II-expressing cell count (Ͼ20-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 (Ͼ20-fold), activation of NFB, and interstitial infiltrations of T cells and macrophages in the remnant kidneys. AT 1 r 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/AT 1 r system and oxidative stress, inflammation, hypertension, and progression of renal disease in rats with renal mass reduction.Significant reduction in renal mass by subtotal nephrectomy or by various disease processes triggers a chain of events that culminates in progressive glomerulosclerosis, tubulointerstitial injury, proteinuria, and end-stage renal disease (Remuzzi et al., 2006). Progressive deterioration of the remnant/diseased kidney function and structure is associated with and largely mediated by profound alteration of renal hemodynamics, inflammation, and oxidative stress (Mackenzie et al., 2000). In this context, renal mass reduction results in glomerular capillary hypertension and glomerular hyperfiltration, which play a major role in the pathogenesis of proteinuria and glomerulosclerosis (Hostetter et al., 2001). This assertion is supported by the observations that prevention/alleviation of the maladaptive hemodynamic alterations by lowering dietary protein or blocking renin-angiotensin system (RAS) decelerates progression of renal disease (Nickenig and Harrison, 1994;Mackenzie et al., 2000). In addition to the hemodynamic factors, accumulation of the inflammatory cells plays a major part in progression of renal disease (Chow et al., 2004;Rodríguez-Iturbe et al., 2004b). This supposition is consistent with the demonstration that inhibition of leukocyte recruitment by chemokine receptor antagonists and treatment with immun...

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

“…36 There is a great deal of evidence implicating that hyperfiltration is associated with increased renal tissue inflammation in experimental animal models. 37,38 Our result were in line with recent report that oxidative stress and inflammation is increased in the contralateral kidney after chronic UUO in the neonatal mice. 39 In conclusion, our results suggest that DPPIV inhibition protects against renal injury in mice via several mechanisms related to fibrosis, inflammation, and oxidative damage, independently of its hypoglycemic effects.…”

Proinflammatory role of angiotensin II in a rat nephrosis model induced by adriamycin

“…Regarding this, similar findings have been reported in other models of neph ropathy. 44 Therefore, AT 1 receptor blockade could be more important than the intrarenal content of Ang II. As an inter esting finding, acellular accumulation of Ang II reactive zones was observed in glomeruli, interstitium and tubular lumen.…”

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…ROS production is markedly increased in the diseased kidney, as well as vascular and various other tissues. This is primarily driven by activation or upregulation of the ROS-producing enzymes (NAD(P)H oxidase (NOX) isoforms, cycloxygenase-2, lipoxygenase, and uncoupled nitric oxide synthase), mitochondrial dysfunction, and endoplasmic reticulum stress [10][11][12][13][14].…”