The role of alpha-smooth muscle actin and platelet-derived growth factor-beta receptor in the progression of renal damage in human IgA nephropathy

Background. The degree of tubulointerstitial damage can be considered a bet ter indicator of renal function outcome in IgA nephropathy (N) than the ext ent of glomerular sclerosis. Materials and Methods: To investigate the pathogenetic mechanisms of inters titial injury in IgAN, we used immunohistochemistry and in situ hybridizati on to evaluate the glomerular and tubolointerstitial expression of PDGF-bet a receptor (R) and alpha -smooth muscle actin (SMA), two markers of mesench ymal cell activation, and correlated these findings with the histopathologi c and clinical features of the disease. We studied 155 IgAN patients, divid ed into three groups based on the histological findings (mild, moderate and severe histological lesions). Results: In normal kidneys and in patients with mild histological lesions, the interstitial areas showed scattered peritubular cells positive for PDGF -betaR and alpha -SMA, with a distribution resembling the capillary network . In the glomeruli several cells (mainly in the mesangial area) stained for PDGF-betaR, but only very few cells were positive for alpha -SMA. Alpha-SM A and PDGF-betaR staining, as expected, was also observed in vascular smoot h muscle cells. Compared to patients with mild histological lesions, alpha -SMA expression was strikingly increased in patients with moderate to sever e lesions, particularly in areas of tubulointerstitial fibrosis. In these p atients, PDGF-betaR gene and protein expression, at the tubulointerstitial level, paralleled that in alpha -SMA. Both signals were significantly corre lated with the interstitial damage (interstitial infiltrate and fibrosis). Interestingly, these patients showed a different pattern of distribution of alpha -SMA and PDGF-betaR in the glomeruli: PDGF-betaR expression was upre gulated, whereas no changes were seen in alpha -SMA staining. In addition, glomerular PDGF-betaR staining was significantly correlated with mesangial cell proliferation, while alpha -SMA was not. Image analysis showed that 40 .2 +/- 10.3/1,000 mum(2) of interstitial cells were positive to both PDGF-b etaR and alpha -SMA, but only 2.8 +/- 1.8/1,000 mum(2) of glomerular cells expressed both signals. Conclusions. Our study supports the hypothesis that interstitial PDGF-betaR and alpha -SMA positive cells may play a key role in the pathogenesis of t ubulointerstitial damage.