Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

Abstract

Adriamycin (ADR)-induced nephropathy in animals is an experimental analog of human focal segmental glomerulosclerosis, which presents as severe podocyte injury and massive proteinuria and has a poorly understood mechanism. The present study was designed to test the hypothesis that the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α-mitochondria axis is involved in ADR-induced podocyte injury. Using MPC5 immortalized mouse podocytes, ADR dose dependently induced downregulation of nephrin and podocin, cell apoptosis, and mitochondrial dysfunction based on the increase in mitochondrial ROS production, decrease in mitochondrial DNA copy number, and reduction of mitochondrial membrane potential and ATP content. Moreover, ADR treatment also remarkably reduced the expression of PGC-1α, an important regulator of mitochondrial biogenesis and function, in podocytes. Strikingly, PGC-1α overexpression markedly attenuated mitochondrial dysfunction, the reduction of nephrin and podocin, and the apoptotic response in podocytes after ADR treatment. Moreover, downregulation of PGC-1α and mitochondria disruption in podocytes were also observed in rat kidneys with ADR administration, suggesting that the PGC-1α-mitochondria axis is relevant to in vivo ADR-induced podocyte damage. Taken together, these novel findings suggest that dysfunction of the PGC-1α-mitochondria axis is highly involved in ADR-induced podocyte injury. Targeting PGC-1α may be a novel strategy for the treatment of ADR nephropathy and human focal segmental glomerulosclerosis.

Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain

“…Although it is generally accepted that an initial injury to podocytes induces proteinuria, the exact pathomechanism of the DXR-induced nephropathy is poorly understood [13]. The role of sustained inflammation and oxidative stress has been demonstrated in many experimental models of renal fibrosis, including the remnant kidney [11,14,15] and DXR nephropathy models [12,16,17,18,19].…”

Protective effect of astragalosides from Radix Astragali on adriamycin-induced podocyte injury

“…The differentiated and mature podocytes were seeded into 96-well plates at a density of 2.0x10 3 per well. After full adherence, cells were treated as aforementioned and each experimental condition was performed in six wells.…”

“…Podocyte injury is considered to be one of the most critical factors in the development of proteinuria caused by glomerular filtration barrier dysfunction and continuous injury may cause severe apoptosis, leading to proteinuria, glomerulosclerosis and renal impairment; the major reason is that podocytes are highly differentiated cells with specific structural and biological functions, which are not renewable after sustained injury (1,2). To date, a large number of studies have indicated that podocyte injury, loss and dysfunction have an important role in pathologies including focal segmental glomerulosclerosis and membranous nephropathy (3)(4)(5). Immunosuppressants (e.g., steroids or cyclosporine A) have been used based on anecdotal evidence to treat NS (6).…”

Podocyte Injury–Driven Lipid Peroxidation Accelerates the Infiltration of Glomerular Foam Cells in Focal Segmental Glomerulosclerosis

“…22,23,41,42 Peroxidized lipid induces the migration of macrophages and both ADR and puromycin aminonucleoside nephrosis directly modify lipid peroxidation by the induction of reactive oxygen species. 43 In addition, ADR might influence not only podocytes but also glomerular endothelial cells and monocyte activation. 44 In this regard, we showed that the HFD/NEP25/LDLR À/À mice with podocyte-selective injury showed a significant amount of glomerular lipid deposition, which inversely correlated with the podocyte number.…”