Journal
KIDNEY INTERNATIONAL
Volume 66, Issue 4, Pages 1403-1416Publisher
ELSEVIER SCIENCE INC
DOI: 10.1111/j.1523-1755.2004.00874.x
Keywords
IgA nephropathy; polymeric IgA; angiotensin II; mesangial cells; angiotensin II subtype-1 receptor; angiotensin II subtype-2 receptor
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angiotensin system (RAS) is detected in glomerular mesangial cells in IgA nephropathy (IgAN). Preliminary studies showed a reduced glomerular gene expression of angiotensin II subtype 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN. Methods. We examined the effect of polymeric IgA1 (pIgA1) from patients with IgAN on the expression of Ang II receptors in cultured human mesangial cells (HMC). Results. Polymeric IgA1 from patients with IgAN down-regulated the expression of AT1R in HMC in a dose-dependent manner. When similar experiments were conducted with addition of an angiotensin-converting enzyme inhibitor (captopril) or an AT1R antagonist (losartan), there was a significant increase in the expression of AT1R. Blockade of Ang II with captopril or losartan alone resulted in a stepwise increase of AT1R in cultured HMC. Down-regulation of Ang II subtype 2 receptor (AT2R) was not observed in HMC cultured with pIgA1 from patients with IgAN. The acute suppressive effect of pIgA1 from IgAN on the expression of AT1R was confirmed in HMC incubated with IgA isolated from 15 IgAN patients, 15 healthy subjects, and other glomerulonephritides control subjects. Reduced glomerular expression of AT1R (but not AT2R) was also demonstrated in renal biopsies from patients with IgAN. Conclusion. Our findings demonstrate an altered AT1R expression in HMC in response to raised intrarenal Ang II in IgAN. Our in vitro studies also support that an imbalance of AT1R and AT2R activity in HMC following exposure to pIgA plays a significant pathogenetic role in the inflammatory injury in IgAN.
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