Podocytes are new cellular targets of hemoglobin-mediated renal damage

Abstract

Recurrent and massive intravascular hemolysis induces proteinuria, glomerulosclerosis and progressive impairment of renal function, suggesting podocyte injury. However, the effects of hemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin-cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway and altered podocyte morphology, with decreased expressionof the slit diaphragm proteins nephrin and synaptopodin. Hb-uptake activated the nuclear factor erythroid-2-related factor 2 (Nrf2) and induced expression of the Nrf2-related antioxidant proteins HO-1 and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular hemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression and podocyte apoptosis. These pathological effects were enhanced in Nrf2-deficient mice, whereas Nrf2 activation with sulforaphane protected podocytes against Hb-toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO-1, ferritin and pNrf2 in renal sections and urinary sediments of patients with massive intravascular hemolysis, such as atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular hemolysis, promoting oxidative stress, podocyte dysfunction and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular hemolysis.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zZG4br