Role of cellular infiltrates in response to proteinuria.
Tubulointerstitial injury caused by multiple insults, including significant proteinuria, results in interstitial inflammation. Evidence supports the hypothesis that interstitial inflammatory cells initially recruited in response to injury subsequently contribute to interstitial fibrosis. Experimental manipulations that decrease the number of interstitial macrophages (Mphis) preserve renal function. Mphis have the potential to secrete a large number of products, including some with fibrosis-promoting effects. Their most potent profibrotic effect may be the production of soluble fibrogenic factors, such as transforming growth factor-ss, endothelin-1, and tumor necrosis factor-alpha. These factors stimulate the synthesis of extracellular matrix proteins by neighboring myofibroblasts. Mphis may also release inhibitors of such matrix-degrading proteases as tissue inhibitor of metalloproteinase-1 and plasminogen activator inhibitor-1. Protease inhibitors have a role in renal scarring by impairing the process of matrix remodeling and degradation, which normally functions in parallel with matrix synthesis. It is predicted that therapeutic interventions that dampen the interstitial inflammatory response will attenuate the renal fibrogenic response, preserving normal renal architecture and function.
Eddy
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Children's Hospital and Regional Medical Center, University of Washington, Seattle, WA, USA. aeddy@u.washington.edu
D000818:Animals; D018450:Disease Progression; D019332:Endothelin-1 / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011507:Proteinuria / Q000150:complications / Q000503:physiopathology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019332:Endothelin-1; D017395:Plasminogen Activator Inhibitor 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta