Key result
In murine models and isolated human cells, AT2R deficiency increased renal fibrosis and fibrocyte infiltration, whereas AT1R inhibition with valsartan reduced fibrosis and fibrocyte numbers.
The renin-angiotensin system regulates renal fibrosis by modulating the number and activation of bone marrow-derived fibrocytes via AT1R and AT2R signaling.
AT2R deficiency may alter fibrocyte-driven renal fibrosis in mice; leaves open human therapeutic relevance.
BACKGROUND: The renin-angiotensin system is a major pathway in the pathogenesis of cardiovascular and renal diseases. Bone marrow-derived fibrocytes, which are dual positive for CD45 and type I collagen, are now considered to contribute to the pathogenesis of various fibrotic diseases. We hypothesized that fibrocytes might contribute to renal fibrosis by an angiotensin II dependent pathway. RESULTS: In murine models of renal fibrosis, angiotensin II type 2 receptor (AT2R)-deficient mice, when compared with wild-type mice, showed increased renal fibrosis and fibrocyte infiltration with a concomitant upregulation of renal transcripts of procollagen type I (alpha) (COL1A1). Fibrocyte numbers in the bone marrow also were increased in AT2R-deficient mice. By contrast, pharmacological inhibition of angiotensin II type 1 receptor (AT1R) with valsartan reduced the degree of renal fibrosis and the number of fibrocytes in both the kidney and the bone marrow. In isolated human fibrocytes, inhibition of AT2R signaling increased the angiotensin II-stimulated expression of type I collagen, whereas inhibition of AT1R decreased collagen synthesis. These results suggest that AT1R/AT2R signaling may contribute to the pathogenesis of renal fibrosis by at least two mechanisms: by regulating the number of fibrocytes in the bone marrow, and by activation of fibrocytes.
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Sakai et al. (2008) studied Renal fibrosis. AT2R deficiency and AT1R inhibition (valsartan) vs. Wild-type mice / untreated cells was evaluated on Renal fibrosis and fibrocyte infiltration. In murine models and isolated human cells, AT2R deficiency increased renal fibrosis and fibrocyte infiltration, whereas AT1R inhibition with valsartan reduced fibrosis and fibrocyte numbers.
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