Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.

Journal Article

Studies in humans and animal models indicate a key contribution of angiotensin II to the pathogenesis of glomerular diseases. To examine the role of type 1 angiotensin (AT1) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Faslpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT1A); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT1A deficiency was not protective against disease but instead substantially accelerated mortality, proteinuria, and kidney pathology. Increased disease severity was not a direct effect of immune cells, since transplantation of AT1A-deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT1B, and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT1A-deficient lpr mice, and they showed evidence of exaggerated AT1B receptor activation, including substantially increased podocyte injury and expression of inflammatory mediators. Administration of losartan, which blocks all type 1 angiotensin receptors, reduced markers of kidney disease, including proteinuria, glomerular pathology, and cytokine mRNA expression. Since AT1A-deficient lpr mice had low blood pressure, these findings suggest that activation of type 1 angiotensin receptors in the glomerulus is sufficient to accelerate renal injury and inflammation in the absence of hypertension.

Full Text

Duke Authors

Cited Authors

  • Crowley, SD; Vasievich, MP; Ruiz, P; Gould, SK; Parsons, KK; Pazmino, AK; Facemire, C; Chen, BJ; Kim, H-S; Tran, TT; Pisetsky, DS; Barisoni, L; Prieto-Carrasquero, MC; Jeansson, M; Foster, MH; Coffman, TM

Published Date

  • April 2009

Published In

Volume / Issue

  • 119 / 4

Start / End Page

  • 943 - 953

PubMed ID

  • 19287096

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI34862

Language

  • eng

Conference Location

  • United States