Transforming growth factor-beta, endothelin-1, and c-fos expression in necrotizing/crescentic IgA glomerulonephritis

Among our cases of IgA glomerulonephritis (IgAGN), 10% show necrotizing/extracapillary lesions involving a small percentage of glomeruli and associated with a certain degree of inflammation in absence of glomerular and interstitial scarring. In our experience, also in repeat biopsies, these cases of IgAGN have a worse prognosis probably because necrotizing/extracapillary lesions can repeat and accumulate, leading to the progression of damage. As it is well known that transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) are key-factors in the progression of glomerulonephritis, aim of the study was to examine their expression in renal biopsies of primary IgAGN with necrotizing/crescentic lesions in complete absence of interstitial fibrosis. To obtain information about the mitogenic effect of ET-1, the expression of c-fos, whose upregulation by ET-1 has been established in culture, was also studied.

Eighteen renal biopsies of patients with necrotizing/crescentic IgAGN were examined by immunohistochemistry with antibodies against TGF-beta, ET-1 and c-fos. The results were compared with those obtained on 22 cases of IgAGN characterized only by pure mesangial proliferation and 25 IgAGN biopsies with advanced, not active, glomerulointerstitial lesions.

In necrotizing/crescentic IgAGN glomerular TGF-beta appeared more positive than in cases characterized only by pure mesangial proliferation and was especially expressed on cellular crescents. In the interstitium, TGF-beta, ET-1 and c-fos were expressed by infiltrating leukocytes, tubules, and small vessels. This positivity, although similar as localization, was less diffuse than in biopsies with advanced interstitial damage, but significantly greater than in cases with pure mesangial proliferation.

Positivity of TGF-beta on cellular crescents is similar to that observed from other authors in different types of necrotizing/crescentic human glomerulonephritis and supports our hypothesis that this is a peculiar type of IgAGN. Moreover, interstitial expression of TGF-beta, ET-1 and c-fos in biopsies with glomerular active lesions but complete absence of interstitial fibrosis may potentially represent a signal of activation of mechanisms that induce and amplify the damage leading to further progression of the disease.