Mechanisms of tubulointerstitial injury in IgA nephropathy

Abstract

IgA nephropathy (IgAN) runs a highly variable clinical course, with frequent involvement of tubulointerstitial damage. A subgroup of IgAN with severe tubulointerstitial damage is often associated with the most rapid progression to end-stage renal failure. In IgAN, mesangial sclerosis and tubulointerstitial damage were found to be correlated with the increase in pore size of the glomerular barrier. The direct toxicity of proximal tubular epithelial cells (PTEC) by IgA in IgAN is still unresolved. Activation of PTEC by mediators released from infiltrating cells or resident kidney cells that induce tubular inflammation is the common final pathway in most chronic renal diseases. We hypothesize that mediators released from human mesangial cells (HMC) triggered by IgA deposition may lead to PTEC activation. We found that IgA binding to PTEC was less than one tenth that of HMC. The binding was nonspecific and exhibited no increased cell proliferation or enhanced synthesis of cytokines or adhesion molecules. However, when PTEC were cultured with IgA-HMC spent medium prepared from IgAN patients, there was enhanced proliferation of PTEC and increased synthesis of cytokines and adhesion molecules. These findings implicate a glomerulotubular cross-talk with mediators released from the mesangium, contributing to the pathogenesis of tubulointerstitial damage in IgAN. There are preliminary data to suggest that the expression of angiotensin II subtype-1 receptor and angiotensin II subtype-2 receptor in PTEC differs from that of HMC. These novel findings may provide clinicians new therapeutic approach for selective blockade of the tubulointerstitial injury in IgAN.