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Polymeric IgA1 from Patients with IgA Nephropathy Upregulates Transforming Growth Factor- Synthesis and Signal Transduction in Human Mesangial Cells via the Renin-Angiotensin System

Kar Neng Lai^*, Sydney C. W. Tang^*, Jinn-Yuh Guh, Tsai-Der Chuang, Man Fai Lam^*, Loretta Y. Y. Chan^*, Anita W. L. Tsang^* and Joseph C. K. Leung^*

*Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, and Department of Internal Medicine, Kaohsiung Medical University, Taiwan.

Correspondence to Dr. Kar Neng Lai, Department of Medicine, Room 409, Professorial Block, Queen Mary Hospital, University of Hong Kong, Hong Kong. Phone: +852-28554251; Fax: +852-28162863; E-mail: knlai{at}hkucc.hku.hk

ABSTRACT. The effects of polymeric IgA1 (pIgA1) and monomeric IgA1 (mIgA1) from patients with IgA nephropathy (IgAN) on the renin-angiotensin system (RAS) and TGF- synthesis were examined in cultured human mesangial cells (HMC). Both pIgA1 and mIgA1 induced renin gene expression in HMC, in a dose-dependent manner. Similar findings were observed for TGF- gene and protein expression. The values measured in HMC incubated with pIgA1 were significantly higher than those in HMC incubated with equivalent amounts of mIgA1. When similar experiments were performed with the addition of either captopril or losartan, there was a significant increase in the renin gene expression by HMC, whereas the synthesis of TGF- was markedly reduced. The TGF- signal transduction pathways in HMC were studied by measuring the receptor-regulated Smad proteins (Smad 2 and 3) and common-partner Smad proteins (Smad 4). pIgA1 from patients with IgAN upregulated Smad activity in HMC, and the activity observed in HMC that had been preincubated with pIgA1 was readily suppressed with optimal concentrations of captopril or losartan. The effects of pIgA1 on the RAS were further examined in HMC incubated with IgA isolated from 30 patients with IgAN, 30 healthy subjects, and disease control subjects with other diseases. pIgA1 induction of angiotensin II or TGF- synthesis in HMC was significantly greater with preparations from patients with IgAN, compared with healthy or disease control subjects. The findings support a pathogenetic role of pIgA1 in IgAN through upregulation of the RAS and TGF-, leading to chronic renal failure with renal fibrosis.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673