TGF-β type II receptor deficiency prevents renal injury via decrease in ERK activity in crescentic glomerulonephritis

The role of transforming growth factor-β (TGF-β) receptor complex in the pathogenesis of crescentic glomerulonephritis (GN) is not clear. To test the hypothesis that TGF-β signaling plays a crucial role in the development and progression of crescentic GN by inducing the activation of extracellular signal-regulated kinase (ERK) and expression of its target genes, anti-glomerular basement membrane (GBM) GN was induced in TGF-β type II receptor (TGF-βIIR) gene heterozygous (TGF-βIIR+/−) C57BL/6J mice and wild-type animals. GN was initiated in preimmunized mice by administration of rabbit anti-mouse GBM serum. TGF-βIIR deficiency was significantly associated with decreased renal damage at days 14, 21, and 28 after induction of GN: renal function impairment, proteinuria, proportion of crescents, glomerular accumulation of periodic acid-Schiff-positive material, relative cortical interstitial volume, as well as renal cortical phosphorylation of ERK and plasminogen activator inhibitor type I (PAI-1) and α2(I) collagen mRNA levels were significantly decreased in TGF-βIIR+/− mice compared with wild-type animals. These results provide the first direct evidence that TGF-βIIR deficiency protects against renal injury in crescentic GN, possibly by inhibiting the sustained activation of ERK and PAI-1 and α2(I) collagen gene expression. Thus, TGF-β signaling appears to play an important role in the development and progression of crescentic GN by inducing the ERK activity, and PAI-1 and α2(I) mRNA expression.