The Role Of CARD9 In The Pathogensis Of IgA Nephropathy

Abstract

IgA nephropathy (IgAN) is a common cause of primary glomerulonephritis worldwide. It is characterised by the deposition of poorly galactosylated IgA1 immune complexes in the renal mesangium, leading to end stage renal damage in 30% of patients. At present, the pathogenesis of IgAN is not well understood. IgAN GWAS studies revealed an association between IgAN and a SNP within the coding sequence of the CARD9 gene. CARD9 is an essential mediator of the innate immune system, however its place in the pathogenesis of IgAN has yet to be defined. The aim of this study was to investigate the role of CARD9 in IgAN.In this project, the expression of CARD9 mRNA was higher in; peripheral blood mononuclear cells (PBMCs) from IgAN patients compared to healthy controls, and in IgAN renal biopsy tissue compared to other renal diseases. rs4077515-T was associated with increased synthesis of IgA and poorly O-galactosylated IgA1 by activated PMBCs from both IgAN patients and healthy subjects. Immunohistochemistry demonstrated CARD9 protein in both the glomerular and tubulointerstitial compartments in IgAN and western blotting revealed the presence of CARD9 in cell lysates from human renal cells. Human mesangial cells with the rs4077515-T allele synthesised significantly more of the pro-inflammatory cytokine IL-6 following exposure to IgA1. Similar increases were seen in mRNA coding for IL-6, IL-6 signal transducer (IL-6ST) and monocyte chemoattractant protein 1(MCP-1), suggesting that the presence of rs4077515-T could result in a greater inflammatory response to mesangial IgA deposition in IgAN. A significant association between rs4077515-T and the likelihood of renal function decline in Chinese IgAN patients was observed.This study provides an insight into the contribution of CARD9 in; the generation of poorly O-galactosylated IgA1 by human PBMCs, the response of mesangial cells to IgA deposition in IgAN, the likelihood of renal function decline in IgAN.