Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis
Steven D. Crowley, … , Mary H. Foster, Thomas M. Coffman
Steven D. Crowley, … , Mary H. Foster, Thomas M. Coffman
Published March 16, 2009
Citation Information: J Clin Invest. 2009;119(4):943-953. https://doi.org/10.1172/JCI34862.
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Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis

Abstract

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.

Authors

Steven D. Crowley, Matthew P. Vasievich, Phillip Ruiz, Samantha K. Gould, Kelly K. Parsons, A. Kathy Pazmino, Carie Facemire, Benny J. Chen, Hyung-Suk Kim, Trinh T. Tran, David S. Pisetsky, Laura Barisoni, Minolfa C. Prieto-Carrasquero, Marie Jeansson, Mary H. Foster, Thomas M. Coffman

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Figure 6

Absence of AT1A receptors on bone marrow–derived cells does not account for the accelerated mortality of lpr-KO mice.

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Absence of AT1A receptors on bone marrow–derived cells does not account ...
(A) Southern blot analysis of genomic DNA isolated from splenocytes, digested with BamH1, and hybridized with a DNA probe that distinguishes the 8.6-kb fragment generated from the wild-type Agtr1a allele and the 3.8-kb fragment identifying the targeted allele (1). Samples: lane 1, nontransplanted MRL-Faslpr/lprAgtr1a+/– control; both bands are present with equal intensities. Lane 2, lpr→lpr, an lpr (MRL-Faslpr/lprAgtr1a+/+) mouse transplanted with lpr bone marrow; only the wild-type band is observed. Lane 3, lpr-KO→lpr, an lpr mouse transplanted with bone marrow from an lpr-KO mouse (MRL-Faslpr/lprAgtr1a–/–); the 3.8 kb band predominates, indicating that the majority of cells in the sample (98.3% by densitometry) come from the donor. (B) Survival of MRL/lpr mice transplanted with wild-type versus Agtr1a–/– bone marrow. Survival of lpr mice (n = 26; 12 males, 14 females) transplanted with bone marrow from lpr donors was virtually identical to the mean survival of lpr animals (n = 32; 17 males, 15 females) transplanted with lpr-KO bone marrow lacking AT1A receptors (230 ± 11 versus 234 ± 8 days; P = NS).