Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice

Diabetic nephropathy (DN) is the major life-threatening com-plication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN path-ogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the GBM. Loss of GBM HS in diabetic kidney was associated with increased glomerular expression of heparanase; however, the causal in-volvement of heparanase in the pathogenesis of DN has not been demonstrated. We report for the first time the essential in-volvement of heparanase in DN. With the use of Hpse-KO mice, we found that deletion of the heparanase gene protects diabetic mice from DN. Furthermore, by investigating the molecular mech-anism underlying induction of the enzyme in DN, we found that transcription factor early growth response 1 (Egr1) is responsible for activation of heparanase promoter under diabetic conditions