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 diseases and histologically characterized by severe glomerulosclerosis and subsequent tubulo-interstitial fibrosis (TIF). In DMS patients, renal dysfunction correlates well with TIF, rather than with glomerular lesions. Thus, molecular mechanisms whereby TIF in DMS progresses should be addressed. Previously, we found that nephrotic ICGN mice manifest DMS-like lesions and develop 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, while the TGF-beta 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 at the late-stage of DMS. As a result, alpha-actin-positive myofibroblastic cells were found dominant in the interstitial spaces of the late-stage DMS mice. Finally, TIF became severe in accordance with the overexpressions of these molecules. Our results suggest that in our murine model: 1) persistent proteinuria leads to over-expression of TGF-beta and PDGF in non-glomerular areas; 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 DMS patients.
Mizuno
S
S
The Institute of Experimental Animal Sciences, Osaka University Medical School, Suita, Japan.
Mizuno-Horikawa
Y
Y
Kurosawa
T
T
D000419:Albuminuria / Q000652:urine; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis / Q000097:blood / Q000473:pathology / Q000652:urine; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000473:pathology* / Q000652:urine; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D009404:Nephrotic Syndrome / Q000097:blood / Q000473:pathology* / Q000652:urine; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D012709:Serum Albumin; D016212:Transforming Growth Factor beta; D003404:Creatinine; D017479:Receptors, Platelet-Derived Growth Factor