The role of IgA in proximal tubular cell activation and tubulointerstitial scarring in IgA nephropathy

Abstract

BackgroundIgA nephropathy (IgAN) is the commonest form of glomerulonephritis worldwide, and around 30% of patients progress to end-stage renal failure within 20 years. One of the most powerful prognostic factors for progression in IgAN is the development of tubulointerstitial inflammation and fibrosis. The extent of tubulointerstitial damage in IgAN does not however correlate with the degree of mesangial IgA deposition. Changes in glomerular permeability in IgAN result in exposure of the proximal tubular epithelium to IgA. It is therefore possible that a pathogenic interaction between filtered IgA and proximal tubular cells drives tubulointerstitial scarring in IgAN, independent of the effect of albuminuria. We aimed to assess the interaction between IgA and proximal tubular cells to establish whether IgA could independently generate a proinflammatory and profibrotic phenotypic transformation in proximal tubular cells thereby favouring the development of renal fibrosis. MethodsIgA1 was purified from serum from patients with IgAN and healthy individuals by jacalin-agarose affinity chromatography. Human proximal tubular epithelial HK2 cells (PTEC) were exposed for 24 h to IgA1 (100 μg/mL) from patients with IgAN or healthy individuals, or to control conditions IgM (100 μg/mL), IgG (100 μg/mL), albumin (100 μg/mL or 5 mg/mL), or medium alone, and then subjected to protein extraction, with supernatants assayed by sandwich ELISA. FindingsIgA1 from patients with IgAN activated extracellular signal-regulated protein kinase in PTEC to a greater extent than did IgM or IgA1 from healthy individuals. IgA1 from patients with IgAN also stimulated PPAR-response-element-driven luciferase expression, indicating PPAR activation. PTEC synthesis of transforming growth factor β, fibronectin, and interleukin 6 was substantially increased by IgA1 (100 μg/mL) compared with IgM, IgG, and albumin at concentrations up to 50 times higher (5 mg/mL). PTEC production of complement component C3 and activation of the complement cascade with generation of the chemotactic component C5a were induced to a greater extent by IgA1 compared with the other conditions. Finally, IgA1 induced phosphorylation of a megalin cytoplasmic tail plus glutathione-s-transferase fusion protein in HK2 cells suggesting that IgA1 binding to PTEC can trigger the same intracellular signalling pathways as those activated after exposure to albumin. InterpretationWe provide evidence that IgA1 in IgAN triggers a proinflammatory and profibrotic phenotypic transformation of PTECs. Interaction between filtered IgA1 and PTEC might be a key factor in driving tubulointerstitial damage and progression of renal fibrosis in IgAN. Further elucidation of the mechanism of this interaction might reveal novel therapeutic targets relevant in slowing progression of IgA nephropathy. FundingUK Medical Research Council.