Mitochondrial Oxidative Stress and Cell Death in Podocytopathies

Abstract

Podocytopathies are kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical presentations. Albeit podocytopathies are the major contributors to end-stage kidney disease, the underlying molecular mechanisms of podocyte injury remain to be elucidated. Mitochondrial oxidative stress is associated with kidney diseases, and increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies. Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research. Excessive generated reactive oxygen species over antioxidant defense under pathological conditions lead to oxidative damage to cellular components and regulate cell death in the podocyte. Conversely, exogenous antioxidants can protect podocyte from cell death. This review provides an overview of the role of mitochondrial oxidative stress in podocytopathies and discusses its role in the cell death of the podocyte, aiming to identify the novel targets to improve the treatment of patients with podocytopathies.

Keywords: antioxidant defense; cell death; mitochondrial oxidative stress; podocytopathies; reactive oxygen species (ROS).

Figure 1

Oxidative stress plays a significant role in the pathogenesis of podocytopathies. Various harmful stimuli, such as puromycin aminonucleoside, immune complexes, HG, and Ang II, upregulate NOX, Cyt C, and P450, and downregulate mitochondrial respiration chain complexes (complex I, II, III, and IV), Ub, and antioxidant defense systems, including SOD, GPX, CAT, GSH, Prdx, and Trx. Excessive ROS accumulation in the podocyte causes damage to DNA, lipids, and proteins, and activates downstream signaling pathways, leading to podocyte foot process effacement, loss, and detachment, with clinical presentations of proteinuria and proteinuria-related symptoms. HG, high glucose; Ang II, angiotensin II; AT1R, angiotensin II type 1 receptor; AOPPs, advanced oxidation protein products; AGEs, advanced glycation end-products; RAGE, receptor of advanced glycation end-products; MC, mineralocorticoid; MR, mineralocorticoid receptor; C5b-9, C5b-9 membrane attack complex; NOX, NADPH oxidase; I, complex I; II, complex II; III, complex III; IV, complex IV; Ub, quinone; Cyt c, cytochrome c; SOD, superoxide dismutase; GPX, glutathione peroxidase; CAT, catalase; GSH, glutathione; Prdx, peroxiredoxin; Trx, thioredoxin; P450, cytochrome P450; and ROS, reactive oxygen species.

Figure 2

Molecular mechanisms for oxidative stress-triggered podocyte apoptosis. Oxidative stress upregulates FasL to activate the CASP8-mediated extrinsic apoptosis pathway. As for intrinsic apoptosis, p53, PI3K/Akt, and P38 MAPK pathways are activated by oxidative stress, and the expression levels of BAX, PUMA, BIM, and Cyt C are elevated, whereas anti-apoptotic BCL2 is reduced. Whereafter, CASP9 is activated to cleave pro-CASP3 to activate CASP3, which ultimately cleaves cellular components and leads to apoptosis. ER stress is also activated, UPR triggers CHOP- and CASP12-dependent apoptosis, and CHOP activation downregulates BCL2, indicating that intrinsic apoptosis is involved. Moreover, oxidative stress activates CASP-independent apoptosis via upregulating AIF. FasL, Fas ligand; CASP, caspase; Cyt C, cytochrome c; BCL2, B-cell lymphoma-2; BIM, BCL2-interacting mediator of cell death; PUMA, p53-upregulated modulator of apoptosis; BAX, BCL2-associated X; ER, endoplasmic reticulum; UPR, unfolded protein response; CHOP, CCAAT/enhancer-binding protein-homologous protein; and AIF, apoptosis-inducing factor.