**1. Introduction**

Podocytopathies are defined as kidney diseases that are driven by podocyte injury with proteinuria and proteinuria-related symptoms as the main clinical features [1]. The incidence of podocytopathies seems to be gradually rising and they are the leading cause of end-stage kidney disease around the world [1,2]. However, efficient therapies for podocytopathies are lacking and current treatment can only retard the progression of diseases. Podocytes are highly specialized epithelial cells that are located in the glomerulus and constitute the filtration barrier with a glomerular basement membrane (GBM) and endothelial cells [2,3]. The interdigitated foot processes and slit diaphragm of podocytes are elementary structures for the selective filtration function of the glomerulus [1]. Excessive stress and harmful stimuli are likely to cause podocyte injury, possibly even death, which is clinically characterized by proteinuria and pathologically characterized by podocyte foot process effacement (FPE), detachment, and loss [1,2]. Considering the poor proliferation capacity of the podocyte, excessive podocyte loss progressively aggravates podocyte damage and eventually leads to global glomerulosclerosis [2]. Understanding how such detrimental stress and stimuli cause podocyte injury can help us to advance our acknowledgement of the mechanisms underlying the occurrence and progression of podocytopathies.

Mitochondrial oxidative stress refers to disrupted redox homeostasis by the elevated generation of reactive oxygen species (ROS) and (or) declined antioxidant defense capacity [4,5]. Increasing evidence suggests that oxidative stress plays a vital role in the pathogenesis of podocytopathies [6–9]. The excessive accumulation of ROS causes damage to intracellular components and impairs the normal structure and function of podocytes [7,8,10–12].

**Citation:** Zhu, Y.-T.; Wan, C.; Lin, J.-H.; Hammes, H.-P.; Zhang, C. Mitochondrial Oxidative Stress and Cell Death in Podocytopathies. *Biomolecules* **2022**, *12*, 403. https://doi.org/10.3390/ biom12030403

Academic Editor: Liang-Jun Yan

Received: 14 December 2021 Accepted: 1 March 2022 Published: 4 March 2022

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Accumulating evidence has placed mitochondrial oxidative stress in the focus of cell death research [4,13]. Classic cell death includes apoptosis, necrosis, necroptosis, pyroptosis, and ferroptosis [14,15]. Under pathological conditions, when redundant ROS-induced damage is beyond the compensatory capacity of podocytes, cell death occurs [8,16–18]. Conversely, the application of exogenous antioxidants can protect podocytes from cell death and improve kidney function [8,19]. Hence, 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 novel targets to improve the treatment of patients with podocytopathies.

## **2. Spectrum of Podocytopathies**

Genetic factors and non-genetic factors, such as immune, infectious, metabolic, and hemodynamic factors, can cause damage to the podocyte [2]. Therefore, podocytopathies can be further divided into genetic and non-genetic podocytopathies on the basis of the causes.

Numerous genetic researches identified many susceptibility genes relevant to podocytopathies, which can be divided into podocyte genes and syndromal non-specific genes in terms of the types of cells that experience genetic variation [1]. For example, genetic variants in *PLCE1* and *WT1*, two podocyte-expressed genes, result in the arrested development of glomeruli and the onset of diffuse mesangial sclerosis [20,21]. *APOL1* podocytopathy is the best studied podocytopathy that is associated with genetic variants of susceptibility genes [1]. In Africans carrying a high frequency of *APOL1* alleles, the prevalence of chronic kidney disease (CKD) is up to 16% [22].

Non-genetic podocytopathies consist of kidney diseases of many distinct causes. Immune injury to the podocyte can induce the development of podocytopathies, such as IgA nephropathy (IgAN), lupus nephritis (LN), and membranous nephropathy (MN) [2]. Metabolic and hemodynamic abnormalities damage the podocyte as well. Long-term poor glucose control and the hemodynamic changes in diabetics contribute to diabetic nephropathy (DN) [1]. Elevated blood pressure and the accompanying hyperfiltration can also induce podocyte injury, which plays an important role in the pathogenesis of hypertensive nephropathy [23]. Podocytopathies caused by infections and nephrotoxic substances are not negligible, for instance, HIV-associated nephropathy and collapsing glomerulopathy induced by pamidronate [24,25].

#### **3. Oxidative Stress in Podocytopathies**

Under physiological conditions, a homeostasis between the production of ROS and the antioxidant defense system exists in the podocyte. ROS are a collection of chemical substances originated from incomplete reduced oxygen, which mainly consist of superoxide anion, hydrogen peroxide (H2O2), singlet oxygen, and hydroxyl radical [13,26]. In the podocyte, ROS mainly come from the mitochondrial respiration chain and NADPH oxidase (NOX) [27–29]. The mitochondrial respiration chain is mainly composed of NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), ubiquinol-cytochrome c reductase (complex III), cytochrome c oxidase (complex IV), cytochrome c (Cyt C), and quinone [30,31]. Mitochondrial respiration chain dysfunction contributes to excessive ROS generation. Antioxidant defense systems are developed in the organism to eliminate ROS generated from various sources. Enzymatic defense systems include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), and thioredoxin reductase (TrxR) [4,32]. Additionally, antioxidants are comprised of ascorbic acid (Vitamin C), α-tocopherol (Vitamin E), glutathione (GSH), thioredoxin, peroxiredoxin (Prdx), and carotenoids [4,32]. When the redox homeostasis is disrupted due to external stimuli under pathological conditions or inherent defects of podocyte, oxidative stress occurs and leads to podocyte injury and renal damage (Figure 1). Stimuli that are harmful to the podocyte, such as puromycin aminonucleoside (PA), high glucose (HG), and angiotensin II (Ang II), can all contribute to the intracellular accumulation of ROS [28,33,34].

**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.

In this section, we discuss and summarize the mechanisms by which ROS production is elevated in podocytopathies.
