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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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Research Article Nephrology Article has an altmetric score of 1

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

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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 3

Kidney injury is augmented in lpr-KO mice.

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Kidney injury is augmented in lpr-KO mice.
   
High-power views of repre...
High-power views of representative glomeruli from H&E-stained sections of kidneys from lpr (A) and lpr-KO (B) mice at 12 weeks of age. Original magnification, ×600. Typical of MRL-Faslpr/lpr mice at this age, glomerular pathology in the lpr group was relatively mild. In contrast, glomeruli from lpr-KO mice showed severe pathology including hypercellularity, focal necrosis, mesangial expansion, and glomerulosclerosis. Representative low-power views of kidneys from lpr (C) and lpr-KO (D) mice. Original magnification, ×200. There was minimal interstitial infiltration in kidneys from lpr mice (C). In contrast, robust mononuclear cell infiltrates were observed in kidneys from lpr-KO animals (D), especially in perivascular regions. Typical small renal arteries from lpr (E) and lpr-KO (F) mice depict preservation of normal structure in the lpr control (E), with abnormal vascular architecture in the lpr-KO mice (F) characterized by inflammation and reactive hyperplasia with thickening and sclerosis of the arterial wall. Original magnification, ×600. (G) Prevalence of vascular pathology in lpr and lpr-KO kidneys comparing medium and large vessels *P < 0.001 and #P = 0.002 versus lpr by χ2 test. n = 19 for lpr group (9 males and 10 females); n = 24 for the lpr-KO group (14 males and 10 females).

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