Umbelliferone attenuates hyperglycemia-induced podocyte injury by preserving slit diaphragm integrity and actin cytoskeletal organization

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Purpose: Podocytes are critical components of the glomerular filtration barrier.Their function depends on the integrity of slit diaphragm proteins and dynamic regulation of the actin cytoskeleton.Hyperglycemia-induced cytoskeletal disruption contributes to podocyte injury and the progression of diabetic nephropathy.Umbelliferone, a natural coumarin derivative, was reported to have cytoprotective effects, but its protective role in podocytes under hyperglycemic conditions is unclear.Methods: Conditionally immortalized podocytes were exposed to high glucose levels (33 mM) in the presence or absence of umbelliferone (1-20 μM).The cell viability was assessed using an MTT assay.The expression of slit diaphragm proteins, actin cytoskeletonrelated proteins, Rho GTPase-related proteins, and tight junction proteins was analyzed by western blotting.The cytoskeletal organization and protein localization were evaluated using immunofluorescence and rhodamine-phalloidin staining.Results: High glucose significantly reduced the podocyte viability and decreased the expression of slit diaphragm proteins, including nephrin, podocin, and CD2-associated protein.Hyperglycemic conditions also disrupted actin cytoskeletal organization, as evidenced by the reduced F-actin and α-actinin-4 expression and disorganized actin filaments.The umbelliferone treatment restored the expression and localization of slit diaphragm proteins and improved the cytoskeletal organization.In addition, umbelliferone reversed the hyperglycemia-induced alterations in RhoA, Rac1, and Cdc42 expression and restored the expression and distribution of the tight junction proteins, ZO-1 and occludin.Conclusion: Umbelliferone attenuated hyperglycemia-induced podocyte injury by preserving the slit diaphragm integrity and stabilizing the actin cytoskeletal organization.These protective effects were associated with the modulation of Rho GTPase-related proteins and the restoration of tight junction integrity, suggesting the potential utility of umbelliferone in preventing podocyte dysfunction under diabetic conditions.