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 (AT 1 ) receptors in glomerular inflammation associated with autoimmune disease, we generated MRL-Fas lpr/lpr (lpr) mice lacking the major murine type 1 angiotensin receptor (AT 1A ); lpr mice develop a generalized autoimmune disease with glomerulonephritis that resembles SLE. Surprisingly, AT 1A 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 AT 1A -deficient bone marrow did not affect survival. Moreover, autoimmune injury in extrarenal tissues, including skin, heart, and joints, was unaffected by AT 1A deficiency. In murine systems, there is a second type 1 angiotensin receptor isoform, AT 1B , and its expression is especially prominent in the renal glomerulus within podocytes. Further, expression of renin was enhanced in kidneys of AT 1A -deficient lpr mice, and they showed evidence of exaggerated AT 1B 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 AT 1A -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.

Natriuretic Peptide Receptor Guanylyl Cyclase-A Protects Podocytes from Aldosterone-Induced Glomerular Injury

“…30 Activated AT1 signaling at podocytes would be sufficient to cause proteinuria and glomerular injury. 31,32 Furthermore, the crosstalk between AngII and GC-A signaling was shown in cultured podocytes. 33 These data suggest that lack of GC-A in the kidney should have a critical role in exaggerated activation of the "local" RAAS, which was abrogated by ARB treatment.…”

Telmisartan Exerts Renoprotective Actions via Peroxisome Proliferator-Activated Receptor-γ/Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1 Receptor Blockade

“…29 We chose AT 1a R-deficient mice, so the AT 1b R-blocking action of losartan may have antiinflammatory effects. Crowley et al 30 showed previously that AT 1b receptor activation increased podocyte injury and expression of inflammatory mediators using AT 1a R-deficient lpr mice. Also, administration of losartan reduced markers of kidney disease, such as proteinuria, glomerular pathology, and inflammatory cytokine expression.…”

Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

“…However, a small number of human trials are ongoing or at early stages, mainly focused on retarding or preventing diabetic nephropathy. The original clinical trials that used angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor antagonists (12) were designed to lower blood pressure and glomerular hyperfiltration, although newer evidence suggests that a major role for the angiotensin receptor, which is widely expressed by the kidney vasculature, perivascular cells, epithelium, and inflammatory leukocytes, is to stimulate inflammatory pathways (18). It is likely therefore that current use of ACEI and angiotensin receptor inhibitors to treat kidney disease is effective at least in part by blocking proinflammatory and profibrotic pathways (7).…”