Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy

Abstract

IgA nephropathy (IgAN) patients with severe tubulointerstitial damage are often associated with more rapid progression to end-stage renal failure. We had demonstrated that a glomerulotubular cross-talk network orchestrates interactions between infiltrating immuno-competent cells and the proximal tubular epithelial cells (PTEC). We had further shown that when compared with sporadic IgAN patients, polymeric IgA1 (pIgA1) from patients with familial IgAN has higher reactivity to mesangial cells [Kidney Int 2009; 75:1330]. In this study, we investigated whether the glomerulotubular interaction in patients with familial IgAN, compared to sporadic IgAN, will enhance the chemotaxis of peripheral blood mononuclear cells (PBMC) towards tubulointerstitium enhancing tubulointerstitial injury. We used an in vitro transwell co-culture system of PTEC and PBMC to investigate the chemotaxis of PBMC towards PTEC following activation by conditioned medium prepared from HMC cultured with pIgA1 from patients with familial IgAN (n=60) or sporadic IgAN (n=43), their asymptomatic relatives (n=181) and healthy subjects (n=43). Compared to sporadic IgAN, PTEC activated by conditioned medium from patients with familial IgAN had elevated mRNA expression of CCL2/MCP-1, CCL5/RANTES and CXCL8/IL-8. In response to conditioned medium from patients with familial IgAN, there was increase transmigration of (i) monocyte, and (ii) CD20+, CD4+ and CD8+ lymphocytes (including CD4/CD8 ratio) were shown by flow cytometry analysis. Interestingly, the percentages of CD25+ monocytes and CD25+ lymphocytes were also increased in experiments with conditioned medium from patients with familial IgAN. The up-regulated CD25 expression in transmigrated PBMC was further demonstrated by quantitative RT-PCR. Our results suggest that PTEC activated by conditioned medium from patients with familial IgAN have higher ability to promote activation and chemotaxis of immunocompetent cells. This enhanced chemotaxis through glomerulotubular interaction in patients with familial IgAN may implicate a relentless progression of familial IgAN.