NDT Advance Access published online on August 6, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn441
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Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy
1 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong 2 Academic Renal Unit, University of Bristol, Bristol, UK 3 Department of Pathology, Chinese University of Hong Kong, Hong Kong
Correspondence and offprint requests to: Kar Neng Lai, Department of Medicine, Room 411, Professorial Block, Queen Mary Hospital, University of Hong Kong, Hong Kong. Tel: +852-28554251; Fax: +852-28162863; E-mail: knlai{at}hkucc.hku.hk
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Abstract |
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Background. We have previously documented that human mesangial cell (HMC)-derived tumour necrosis factor-
(TNF-) is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the function of podocytes in IgAN.
Methods. Podocyte markers were examined in renal tissues by immunofluorescence. In vitro experiments were conducted with podocytes cultured with polymeric IgA (pIgA) or conditioned medium prepared from HMC incubated with pIgA (IgA–HMC conditioned medium).
Results. Glomerular immunostaining for nephrin or ezrin was significantly weaker in patients with IgAN. The immunostaining of IgA and nephrin was distinctly separate with no co-localization. In vitro experiments revealed no effect of pIgA on the expression of these podocyte proteins as IgA from IgAN patients did not bind to podocytes. In contrast, IgA conditioned medium prepared from IgAN patients down-regulated the expression of these podocyte proteins as well as other podocyte markers (podocin and synaptopodin) in cultured podocytes. The mRNA expression of nephrin, erzin, podocin but not synaptopodin correlated with the degree of proteinuria and creatinine clearance. The down-regulation was reproducible in podocytes cultured with TNF- or transforming growth factor-β (TGF-β) at concentration comparable to that in the IgA–HMC conditioned medium. The expression of these podocyte proteins was restored partially with a neutralizing antibody against TNF- or TGF-β and fully with combination of both antibodies.
Conclusion. Our finding suggests podocyte markers are reduced in IgAN. An in vitro study implicates that humoral factors (predominantly TNF- and TGF-β) released from mesangial cells are likely to alter the glomerular permeability in the event of proteinuria and tubulointerstitial injury in IgAN.
Keywords: IgA nephropathy; podocytes; slit diaphragm; transforming growth factor-β; tumour necrosis factor-
Received for publication: 7. 1.08
Accepted in revised form: 9. 7.08