title: Role of heparanase-driven inflammatory cascade in pathogenesis of diabetic nephropathy.
abstract: Renal involvement is a major medical concern in the diabetic population, and with the global epidemic of diabetes, 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 individuals with DN. These events are fueled by heterotypic interactions among 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 posttranslationally 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 the proper design and future implementation of heparanase-targeting therapeutic interventions (which are currently under intensive development and clinical testing) in individuals with DN and perhaps other complications of diabetes.
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Goldberg
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ariel M
authors.initials: AM
authors.lastname: Rubinstein
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Natali
authors.initials: N
authors.lastname: Gil
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Esther
authors.initials: E
authors.lastname: Hermano
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Li
authors.affiliation: Nephrology Research Laboratory, Department of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Atzmon
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Amichay
authors.initials: A
authors.lastname: Meirovitz
authors.affiliation: Sharett Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel melkin@hadassah.org.il.
authors.forename: Michael
authors.initials: M
authors.lastname: Elkin
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000276:immunology; D020869:Gene Expression Profiling; D005966:Glucuronidase / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase