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The molecular mechanisms of heparan sulfate proteoglycan downregulation in the glomerular basement membrane (GBM) of the kidneys with diabetic nephropathy remain controversial. In the present study, we showed that the expression of heparanase-1 (HPR1), a heparan sulfate-degrading endoglycosidase, was upregulated in the renal epithelial cells in the kidney with diabetic nephropathy. Urinary HPR1 levels were elevated in patients with diabetic nephropathy. In vitro cell culture studies revealed that HPR1 promoter-driven luciferase reporter gene expression, HPR1 mRNA, and protein were upregulated in renal epithelial cells under high glucose conditions. Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression. HPR1 inhibitors were able to restore cell surface heparan sulfate expression. Functional analysis revealed that renal epithelial cells grown under high glucose conditions resulted in an increase of basement membrane permeability to albumin. Our studies suggest that loss of heparan sulfate in the GBM with diabetic nephropathy is attributable to accelerated heparan sulfate degradation by increased HPR1 expression. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a common clinical problem after solid organ transplantation. Whether patients have preexisting diabetes or develop posttransplant diabetes, insulin therapy is usually required. Achieving excellent diabetic control is an important target in reducing the incidence of cardiovascular disease after transplantation., Methods: The authors treated 18 patients with type 2 diabetes after transplantation with rosiglitazone. Eleven patients had preexisting type 2 diabetes and seven patients developed posttransplant diabetes. Rosiglitazone was added to insulin or glyburide to improve elevated hemoglobin Hb A1C levels in patients with preexisting diabetes or was used to try to avoid insulin therapy in posttransplant diabetics. Blood levels of cyclosporine, tacrolimus, creatinine, and HbA1C were followed for a mean of 381 days (range, 133-718 days)., Results: The addition of rosiglitazone did not cause any significant changes in serum creatinine, cyclosporine, or tacrolimus. There were no significant changes in cyclosporine or tacrolimus doses. Mean HbA1C improved from 8.1+/-1.5% to 6.9+/-1.3% (P =0.01) in the 18 patients and from 8.6+/-1.5% to 6.7+/-0.5% (P =0.035) in the 7 patients with posttransplant diabetes. All patients with posttransplant diabetes were well controlled without insulin therapy., Conclusions: Rosiglitazone is a safe and effective oral agent for the treatment of diabetes mellitus after solid organ transplantation. It is the first agent to allow successful oral therapy for patients with posttransplant diabetes, and is a well-tolerated alternative to insulin for these patients.