We have previously shown that human mesangial cell (HMC)-derived tumor necrosis factor- (TNF-) mediates the glomerulo-tubular communication in the development of tubulointerstitial damage in IgA nephropathy (IgAN). Herein, we examine the pathophysiological role of podocytes in IgAN as podocytes are strategically positioned in the glomerulo-tubular axis. In vitro studies demonstrated no binding of podocytes to IgA isolated from IgAN patients nor did podocytes express known IgA receptors. Podocytes cultured with IgA from IgAN patients did not enhance release of growth factors or cytokines. In contrast, podocytes incubated with IgA-conditioned medium (IgA-HMC medium) prepared by culturing HMC with IgA from patients with IgAN for 48 hours exhibited increased gene expression and protein synthesis of TNF-. The enhanced TNF- synthesis by podocytes was only abolished by a neutralizing antibody against TNF- but not by neutralizing antibodies against other cytokines released by activated HMC. TNF- synthesis by podocytes was enhanced by exogenous TNF- in an autocrine fashion. Histological examination revealed podocytes expressed both TNF- receptors (TNF-R1 and TNF-R2) constitutively. Both receptors were up-regulated in podocytes of IgAN patients. In vitro study showed the receptor expression was readily up-regulated by IgA-HMC medium from IgAN patients but not with IgA alone. Increased interleukin 6 synthesis was associated with enhanced TNF-R1 expression in podocytes following stimulation by IgA-HMC medium from IgAN patients. In conclusion, our finding suggests podocytes play a contributory role in the development of interstitial damage in IgAN by activating renal tubular epithelial cells with enhanced TNF- synthesis following inflammatory changes of HMC.