GLOMERULOSCLEROSIS, ARTERIOSCLEROSIS, AND VASCULAR GRAFT STENOSIS - TREATMENT WITH ORAL HEPARINOIDS

At present there is no known treatment for established glomerulosclero sis or atherosclerosis. Since the principal lesion in glomeruloscleros is involves mesangial cells, a vascular smooth muscle cell, we searche d for new therapeutic approaches affecting vascular smooth muscle func tion, especially with respect to modifying the turnover of extracellul ar matrix. We used mice transgenic for bovine growth hormone (bGH), si nce these mice develop end-stage renal disease due to progressive glom erulosclerosis. We previously showed that the subcutaneous injection o f a non-anticoagulant heparin reduced glomerulosclerosis in bGH mice. Since injectable drugs are not a practical means of controlling glomer ulosclerosis in humans, we assessed oral heparin-like compounds and fo und that oral pentosan polysulfate (PPS) reduced glomerulosclerosis in bGH mice at non-toxic doses. Because the positive therapeutic respons e in the bGH model could have been principally hormone-mediated, we ex amined other models of non-immune mediated glomerulosclerosis, includi ng ROP Os/+ non-diabetic and diabetic mice. We found that an oral PPS (Elmiron), which is approved for other indications in humans, reduced sclerosis in all of these forms of chronic, progressive glomeruloscler osis. Based on the similarity of the cellular events in glomeruloscler osis and arteriosclerosis, we assessed the effect(s) of PPS in congeni tal (Watanabe rabbits) and induced (New Zealand White lipid-fed rabbit s) models of arteriosclerosis. The extent and severity of the lesions was significantly reduced in both models by PPS treatment. Finally, we asked whether the proliferative and sclerotic lesion, which is the ca use of vascular graft stenosis, might also respond to PPS treatment. T o do this we cultured cells from the materials removed from stenotic a rteriovenous grafts in hemodialysis patients. We found that PPS inhibi ts the proliferation and matrix production in a dose-dependent manner.