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 better indicator of renal function outcome in IgA nephropathy (N) than the extent of glomerular sclerosis. Materials and Methods: To investigate the pathogenetic mechanisms of interstitial injury in IgAN, we used immunohistochemistry and in situ hybridization to evaluate the glomerular and tubolointerstitial expression of PDGF-beta receptor (R) and alpha -smooth muscle actin (SMA), two markers of mesenchymal cell activation, and correlated these findings with the histopathologic and clinical features of the disease. We studied 155 IgAN patients, divided 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-SMA and PDGF-betaR staining, as expected, was also observed in vascular smooth muscle cells. Compared to patients with mild histological lesions, alpha -SMA expression was strikingly increased in patients with moderate to severe lesions, particularly in areas of tubulointerstitial fibrosis. In these patients, PDGF-betaR gene and protein expression, at the tubulointerstitial level, paralleled that in alpha -SMA. Both signals were significantly correlated 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 upregulated, 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-betaR 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 tubulointerstitial damage.