Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes mellitus, diabetic nephropathy (DN) became the leading cause of end stage renal failure in the Western world. Heparanase (the only known mammalian endoglycosidase that cleaves heparan sulfate) is essentially involved in DN pathogenesis. Nevertheless, the exact mode of heparanase action in sustaining the pathology of DN remains unclear. Here we describe a previously unrecognized combinatorial circuit of heparanase-driven molecular events promoting chronic inflammation and renal injury in DN. These events are fueled by heterotypic interactions between glomerular, tubular and immune cell compartments, as well as diabetic milieu (DM) components. We found that under diabetic conditions latent heparanase, overexpressed by glomerular cells and post-translationally activated by Cathepsin L of tubular origin, sustains continuous activation of kidney-damaging macrophages by DM components, thus creating chronic inflammatory conditions and fostering macrophage-mediated renal injury.
Elucidation of the mechanism underlying the enzyme action in diabetic kidney damage is critically important for proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in DN and perhaps other complications of diabetes.
RG and AMR contributed equally to this work
- Received January 1, 2014.
- Accepted July 2, 2014.
- © 2014 by the American Diabetes Association.
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