Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure.

IgA nephropathy (IgAN) runs a highly variable clinical course with frequent involvement of tubulointerstitial damage. Notably, renal progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions In IgAN. Mesangial IgA deposition induces local release of cytokines, complement, and angiotensin II leading to glomerular inflammation. It remains unclear how mesangial IgA deposition leads to tubulointerstitial injury in IgAN. Moreover, IgA deposits are rarely detected in renal interstitium in IgAN. We hypothesize that mediators released from mesangial cells triggered by IgA deposition leads to activation of proximal tubular epithelial cells. Our preliminary findings implicate a glomerulotubular cross talk with mediators released from the mesangium contributing to the pathogenesis of tubulointerstitial damage in IgAN. We have also found the expression of angiotensin II subtype-1 receptor or angiotensin II subtype-2 receptor in proximal tubular epithelial cells differs from that of mesangial cells. One potential therapeutic approach is to counterbalance the growth-stimulatory effects of angiotensin II through subtype-1 receptor in tubular epithelial cells by subtype-2 receptor-mediated apoptosis and growth inhibition. These novel findings may provide clinicians new therapeutic approach for selective blockade of the RAS in IgAN.