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Mesangial cell Diabetes Proliferating cell nuclear antigen alpha-Smooth muscle actin Type IV collagen Diabetic nephropathy Heparin
Abstract
At present, it is not clear whether mesangial proliferation underlies mesangial expansion in diabetic nephropathy. To address this issue and the relationship between heparin's renoprotective and antimitogenic activities, we studied three streptozotocin-induced diabetic rat groups 5 and 12 months after diabetes induction: two groups were administered a modified heparin, each with a different protocol, and two healthy rat groups, one of which was treated with the same heparin, served as controls. Untreated diabetic animals developed clear evidence of nephropathy, namely expansion of the glomerular extracellular matrix, as expressed by glomerular basement membrane thickening, and increased mesangial deposition of type IV collagen. These alterations were prevented/cured by heparin treatment. Kidney sections were processed immunohistochemically for proliferating cell nuclear antigen and smooth muscle cc-actin which is expressed only by proliferating mesangial cells. The number of proliferating cell nuclear antigen positive nuclei and alpha-actin-positive cells per glomerulus did not differ between groups at both 5 and 12 months. In conclusion, there is no evidence that mesangial proliferation is increased in late experimental diabetic nephropathy, and heparin seems to be renoprotective through mechanisms other than antiproliferation.
Introduction
The anatomical hallmarks of diabetic nephropathy include glomerular basement membrane (GBM) thickening, mesangial expansion, and sclerosis. Although mesangial expansion seems to be primarily due to the accumulation of extracellular matrix, it is unclear whether mesangial cell proliferation also occurs in the diabetic kidney. The observation that many peptides that modulate mitogenesis also affect matrix synthesis suggests that the two phenomena are linked. This thesis is supported by findings in the anti-Thy-1.1-antibody-induced rat glomerulonephritis model [1]; in the glomerulosclerotic kidney of mice transgenic for growth hormone or growth hormone releasing factor [2], and in the rat remnant-kidney model [3]. It has been advanced that diabetic nephropathy constitutes another example of this sequence of events [4].
To investigate this hypothesis and the general one that glomerular scarring requires resident glomerular cell proliferation [4, 5], we reanalyzed previously reported data [6] and correlated the results with new observations on mesangial cell proliferation and our preceding findings on matrix synthesis [7].
Mesangial proliferation was evaluated by examining the proliferating cell nuclear antigen (PCNA) [8]...