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      Angiotensin-(1–7) and the G Protein-Coupled Receptor Mas Are Key Players in Renal Inflammation

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          Abstract

          Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1–7) by interacting with the G protein-coupled receptor Mas may also have important biological activities.

          In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1–7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-κB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1–7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1–7)-mediated NF-κB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-κB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney.

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          Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis.

          Aroon D Hingorani, R MacAllister, Patrick Vallance … (2005)
          A consensus has emerged that angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) have specific renoprotective effects. Guidelines specify that these are the drugs of choice for the treatment of hypertension in patients with renal disease. We sought to determine to what extent this consensus is supported by the available evidence. Electronic databases were searched up to January, 2005, for randomised trials assessing antihypertensive drugs and progression of renal disease. Effects on primary discrete endpoints (doubling of creatinine and end-stage renal disease) and secondary continuous markers of renal outcomes (creatinine, albuminuria, and glomerular filtration rate) were calculated with random-effect models. The effects of ACE inhibitors or ARBs in placebo-controlled trials were compared with the effects seen in trials that used an active comparator drug. Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk of 0.71 (95% CI 0.49-1.04) for doubling of creatinine and a small benefit on end-stage renal disease (relative risk 0.87, 0.75-0.99). Analyses of the results by study size showed a smaller benefit in large studies. In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (1.09, 0.55-2.15), end-stage renal disease (0.89, 0.74-1.07), glomerular filtration rate, or creatinine amounts. Placebo-controlled trials of ACE inhibitors or ARBs showed greater benefits than comparative trials on all renal outcomes, but were accompanied by substantial reductions in blood pressure in favour of ACE inhibitors or ARBs. The benefits of ACE inhibitors or ARBs on renal outcomes in placebo-controlled trials probably result from a blood-pressure-lowering effect. In patients with diabetes, additional renoprotective actions of these substances beyond lowering blood pressure remain unproven, and there is uncertainty about the greater renoprotection seen in non-diabetic renal disease.
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            NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy.

            Sergio Mezzano, Claudio Aros, Alejandra Droguett … (2004)
            Nuclear factor-kappaB (NF-kappaB) regulates genes involved in renal disease progression, such as the chemokines monocyte chemoattractant protein-1 (MCP-1) and RANTES. NF-kappaB is activated in experimental models of renal injury, and in vitro studies also suggest that proteinuria and angiotensin II could be important NF-kappaB activators. It has been proposed that locally produced MCP-1 may be involved in the development of diabetic nephropathy (DN). We examined the hypothesis that NF-kappaB could be an indicator of renal damage progression in DN. Biopsy specimens from 11 patients with type 2 diabeties and overt nephropathy were studied by southwestern histochemistry for the in situ detection of activated NF-kappaB. In addition, by immunohistochemistry and/or in situ hybridization, we studied the expression of MCP-1 and RANTES, whose genes are regulated by NF-kappaB. NF-kappaB was detected mainly in cortical tubular epithelial cells and, to a lesser extent, in some glomerular and interstitial cells. A strong upregulation of MCP-1 and RANTES was observed in all the cases, mainly in tubular cells, and there was a strong correlation between the expression of these chemokines and NF-kappaB activation in the same cells, as observed in serial sections (r = 0.7; P = 0.01). In addition, the tubular expression of these chemokines was correlated mainly with the magnitude of the proteinuria (P = 0.002) and with interstitial cell infiltration (P<0.05). The activation of NF-kappaB and the transcription of certain pro-inflammatory chemokines in tubular epithelial cells are markers of progressive DN. Proteinuria might be one of the main factors inducing the observed pro-inflammatory phenotype.
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              Progression in chronic kidney disease.

              James A. Eddy (2005)
              The pathogenic mechanisms that lead to chronic kidney disease (CKD) converge on a common pathway that results in progressive interstitial fibrosis, peritubular capillary loss with hypoxia, and destruction of functioning nephrons because of tubular atrophy. Interstitial recruitment of inflammatory leukocytes and myofibroblasts occurs early in kidneys destined to develop fibrosis. Circulating monocytes are recruited by locally secreted chemoattractant molecules, facilitated by leukocyte adhesion molecules. Functionally heterogeneous macrophages secrete many fibrosis-promoting molecules, but under some circumstances they may also serve a protective scavenging role. Excessive extracellular matrix production occurs primarily within interstitial myofibroblasts, a population of cells that appears to have more than 1 origin, including the resident interstitial fibroblasts, trans-differentiated tubular epithelial cells, and bone marrow-derived cells. Impaired activity of the endogenous renal matrix-degrading proteases may enhance interstitial matrix accumulation, but the specific pathways that are involved remain unclear. Tubules, inflammatory cells, and myofibroblasts synthesize the molecules that activate the fibrogenic cascades, the most important of which is transforming growth factor beta (TGF-beta). TGF-beta may direct cells to assume a pro-fibrotic phenotype or it may do so indirectly after stimulating synthesis of other fibrogenic molecules such as connective tissue growth factor and plasminogen activator inhibitor-1. Reduced levels of antifibrotic factors that are normally produced in the kidney such as hepatocyte growth factor and bone morphogenic protein-7 may accelerate fibrosis and its destructive consequences. Development of new therapeutic agents for CKD looks promising, but several agents that target different components of the fibrogenic cascade will almost certainly be necessary.
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2009
                Publication date (Electronic): 30 April 2009
                Volume: 4
                Issue: 4
                Electronic Location Identifier: e5406
                Affiliations
                [1 ]Cellular Biology in Renal Diseases Laboratory, Fundación Jimenez Diaz, Universidad Autónoma Madrid, Madrid, Spain
                [2 ]Department of Obstetrics, University of Leipzig, Leipzig, Germany
                [3 ]Department of Cardiology, Charité, Campus Benjamin Franklin (CBF), Berlin, Germany
                [4 ]Institute for Veterinary Pathology, Freie Universität, Berlin, Germany
                [5 ]Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
                [6 ]Centre for Biomedical Research, Hull York Medical School, University of Hull, Hull, United Kingdom
                [7 ]Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile
                L'Istituto di Biomedicina ed Immunologia Molecolare, Consiglio Nazionale delle Ricerche, Italy
                Author notes

                Conceived and designed the experiments: JE HPS MRO TW. Performed the experiments: VE SHW ASK RdB SvdE YW SM. Analyzed the data: VE SHW ASK RdB MRO.

                Article
                Publisher ID: 08-PONE-RA-05391R1
                DOI: 10.1371/journal.pone.0005406
                PMC ID: 2672164
                PubMed ID: 19404405
                SO-VID: 47ac5d0e-9a49-448b-9404-7cd046de289d
                Copyright © Esteban et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 7 July 2008
                Date accepted : 2 February 2009
                Page count
                Pages: 12
                Categories
                Subject: Research Article
                Subject: Nephrology/Acute Renal Failure
                Subject: Nephrology/Acute Renal Failure
                Subject: Nephrology/Chronic Kidney Disease
                Subject: Nephrology/Chronic Kidney Disease
                Subject: Nephrology/Renal Physiology
                Subject: Nephrology/Renal Physiology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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