Background: The pathogenesis of glomerulosclerosis and tubulointerstitial fibrosis in proteinuric renal disease is obscure. We recently showed that transferrin, a key proteinuric component, mediates proximal tubular epithelial cell (PTEC) C3 synthesis. To further examine whether proteinuric tubular injury may induce glomerular inflammation and to characterize the role of transferrin in activating PTEC, glomerular mesangial cells (MC) were exposed to transferrin-activated PTEC culture supernatant and their proliferative and profibrotic responses analyzed.
Methods: Human PTEC and MC were obtained by primary culture. Confluent, transferrin-stimulated PTEC were grown in serum-free medium to produce a "conditioned" medium that was incubated with quiescent MC. The proliferative response of MC was then assessed by thymidine uptake, and the expression of fibrogenic factors measured by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The chemokine profile in PTEC after transferrin treatment was examined by RT-PCR and ELISA.
Results: "Conditioned" supernatant from PTEC, which contained the highest amounts of platelet-derived growth factor (PDGF), stimulated MC proliferation compared with serum-free (P = 0.03) or transferrin-containing (P = 0.009) control media. This proliferative response was partially abrogated by treating MC with anti-PDGF. MC expression of PDGF, but not transforming growth factor-beta or intercellular cell adhesion molecule-1, was up-regulated by conditioned PTEC medium. Transferrin up-regulated monocyte chemoattractant peptide-1, interleukin-8, and macrophage migration inhibitory factor expression in a time- and dose-dependent fashion, but had no effect on RANTES expression by PTEC.
Conclusions: These results provide experimental evidence suggesting that there is a tubuloglomerular "cross-talk" mechanism in the proteinuric state. PTEC-secreted PDGF, which further induces mesangial PDGF, could partially account for the mesangial proliferation frequently observed in proteinuric renal disease. Transferrin is one of the culprit nephrotic proteins leading to tubular overexpression of various proinflammatory chemokines, which may explain the interstitial changes observed in proteinuric states.