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Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT_1A and AT_1B double-knockout mice

¹Division of Nephrology, Department of Medicine, University of Florida, Gainesville, Florida; ²Department of Medicine, Duke University, and Durham Veterans Affairs Medical Centers, Durham, North Carolina; ³Department of Nephrology, Ignacio Chavez, Mexico City, Mexico; and ⁴Nephrology Service, Hospital Universitario, Maracaibo, Venezuela

Submitted 6 April 2005 ; accepted in final form 27 May 2005

AT₁ double receptor (AT_1A and AT_1B) 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) vs. double-knockout mice (n = 6) at 3–5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT₁ double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-, 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- and TNF- mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with 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), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT₁ double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT₂ receptor mRNA expression was not significantly different from wild-type mice. In conclusion, 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.

endothelin; cyclooxygenase-2; NADPH oxidase

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