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1 Division of Nephrology, Department of Medicine, University of Florida, Gainesville, Florida, USA
2 Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC, USA
3 Department of Nephrology, Ignacio Chavez, Mexico City, Mexico
4 Nephrology Service, Hospital Universitario, Maracaibo, Venezuela
* To whom correspondence should be addressed. E-mail: ouyangx{at}medicine.ufl.edu.
AT1 double receptor (AT1A and AT1B) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT1 double-knockout mice. We examined the renal expression of various mediator systems in control (n=6) versus double-knockout mice (n=6) at 3-5 months of age by real-time PCR, immunohistochemistry and Western analysis. AT1 double-knockout mice show activation of Th1 dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4+ and CD11b+ cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared to controls (p<0.05 for all markers). These changes were associated with increased mRNA expression of endothelin ET-1 and ET-A receptor (P<0.05), but not ET-B, COX-2/ TXA2 synthase (p<0.05), NADPH oxidase (p40-phox, p67-phox, P<0.05) and with iNOS and nNOS (p <0.05). COX2 and nNOS protein were also increased in the kidneys of AT1 double-knockout mice by Western Blot (p<0.05). While renin and angiotensinogen mRNA expression were increased in the knockout mice, AT2 receptor mRNA expression was not significantly different from wildtype mice. In conclusions, the absence of the AT1 receptor is associated with marked renal alterations in vasoactive, profibrotic and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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