title: Urinary podocyte microparticles identify prealbuminuric diabetic glomerular injury.
abstract: Microparticles (MPs) are small (0.1-1.0 µm) vesicles shed from the surface of cells in response to stress. Whether podocytes produce MPs and whether this production reflects glomerular injury are unclear. We examined MP formation in cultured human podocytes (hPODs) and diabetic mice. hPODs were exposed to cyclical stretch, high glucose (HG; 25 mM), angiotensin II, or TGF-β. Urinary podocyte MPs were assessed in three mouse models of diabetic nephropathy: streptozotocin (STZ)-treated, OVE26, and Akita mice. Cyclic stretch and HG increased MP release as assessed by flow cytometry (P<0.01 and P<0.05, respectively, versus controls). Inhibition of Rho-kinase (ROCK) with fasudil blocked HG-induced podocyte MP formation. STZ-treated (8 weeks) mice exhibited increased urinary podocyte MPs compared with age-matched nondiabetic mice. Similarly, 16-week-old OVE26 mice had elevated levels of urinary podocyte MPs compared with wild-type littermates (P<0.01). In 1 week post-STZ-treated and 6- and 12-week-old Akita mice, urinary podocyte MPs increased significantly compared with those MPs in nondiabetic mice, despite normal urinary albumin levels. Our results indicate that podocytes produce MPs that are released into urine. Podocyte-derived MPs are generated by exposure to mechanical stretch and high glucose in vitro and could represent early markers of glomerular injury in diabetic nephropathy.
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and.
authors.forename: Dylan
authors.initials: D
authors.lastname: Burger
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Thibodeau
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and.
authors.forename: Chet E
authors.initials: CE
authors.lastname: Holterman
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Kidney Research Centre, Division of Nephrology, Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and ckennedy@uottawa.ca.
authors.forename: Christopher R J
authors.initials: CR
authors.lastname: Kennedy
mesh_terms: D000419:Albuminuria; D000818:Animals; D055252:Cell-Derived Microparticles; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology*; D006801:Humans; D007678:Kidney Glomerulus / Q000648:ultrastructure*; D051379:Mice; D050199:Podocytes / Q000648:ultrastructure*