Immunohistochemical analysis of molecular events in tubulo-interstitial fibrosis in a mouse model of diffuse mesangial sclerosis (ICGN strain)

Diffuse mesangial sclerosis (DMS) is one of the hereditary glomerular disea ses and histologically characterized by severe glomerulosclerosis and subse quent tubulo-interstitial fibrosis (TIF). In DMS patients, renal dysfunctio n correlates well with TIF, rather than With glomerular lesions. Thus, mole cular mechanisms whereby TIF in DMS progresses should be addressed. Previou sly, we found that nephrotic ICGN mice manifest DMS-like lesions and develo p renal dysfunction in accordance with onset of TIF. In the present study, we investigated fibrogenic events involved in the progression of TIF after DMS manifestation, using the DMS mouse model. Immunohistochemistry revealed that expression of transforming growth factor-beta (TGF-beta) was rare in the interstitial cells of the nephrotic mice at the early-stage of DMS, whi le the TGF-P expression became evident in the late-stage DMS mice. Platelet -derived growth factor (PDGF) was mildly expressed in the distal tubules of the early-stage DMS mice, whereas the PDGF expression markedly increased a t the late-stage of DMS. As a result, a-actin-positive myofibroblastic cell s were found dominant in the interstitial spaces of the late-stage DMS mice . Finally, TIF became severe in accordance with the overexpressions of thes e molecules. Our results suggest that in our murine model: 1) persistent pr oteinuria leads to over-expression of TGF-P and PDGF in non-glomerular area s; 2) these cytokines provoke interstitial myofibroblast accumulation; and 3) the myofibroblasts produce fibrotic matrix proteins in the interstitial spaces. This process may possibly contribute to the development of TIF in D MS patients.