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.

Transforming growth factor beta (TGF-β) signaling is the master modulator of renal fibrosis. However, targeting drugs have failed to prevent the progression of chronic kidney disease (CKD) in clinical trials due to the extensive biological regulation of TGF-β signaling. It is necessary to investigate the precise downstream mechanisms of TGF-β signaling that regulate renal fibrosis. In this study, we found that PR-domain containing 16 (PRDM16) expression in human renal tubular epithelial cells was markedly reduced by TGF-β. Mechanistically, activated Smad3 induced by TGF-β interacted with the cofactor H-Ras and bound to the promoter of PRDM16, downregulating its transcription. Tubular-specific knockout of PRDM16 promoted renal fibrosis in models of unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (UIRI) by exacerbating mitochondrial dysfunction. In vitro, PRDM16 blocked TGF-β-induced mitochondrial injury and lipid deposition by upregulating Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α). Delivery of the exogenous PRDM16 gene preserved renal function and ameliorated the progression of renal fibrosis by protecting mitochondrial function. We report PRDM16 as a novel downstream target of TGF-β signaling that attenuates renal fibrosis by safeguarding tubular mitochondrial function.

Objective: To assess the significance of focal segmental glomerulosclerosis (FSGS) variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy (IMN) patients. Methods: The clinicopathological data of 146 IMN patients diagnosed between December 2016 and March 2019 in our center were collected and analyzed. These patients were divided into the pure IMN group, IMN with glomerular tip lesion (GTL) group, and IMN with non-GTL FSGS group. Results: The IMN with non-GTL FSGS and IMN with GTL groups both had higher proportions of patients with hypertension, lower serum albumin, and severe proteinuria, while the IMN with non-GTL FSGS group additionally showed higher blood pressure and serum cholesterol, and lower serum IgG than the IMN group (all P<0.05). As for pathology, the IMN with non-GTL FSGS group had higher proportions of patients with acute tubular injury and moderate to severe chronic injuries than the IMN group (all P<0.05). In the IMN, IMN with GTL, and IMN with non-GTL FSGS groups, the overall one-year remission rates were 81.6%, 76%, and 58.8%, respectively. Furthermore, the IMN with non-GTL FSGS group showed the lowest cumulative incidence to reach remission within one year. Multivariate Cox logistic analysis demonstrated that higher level of serum anti-M-type phospholipase A2 receptor antibody and the existence of non-GTL FSGS lesion were independent predictors for no remission in IMN patients. Conclusion: The non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.

Chronic stress is a pervasive psychophysiological burden and an independent risk factor for chronic kidney disease (CKD). Large-scale cohort studies confirm that stress exposure significantly increases CKD risk and accelerates renal decline, even after adjusting for traditional confounders. However, the neuroendocrine mechanisms translating stress into direct kidney damage remain unclear. This review focuses on the brain–kidney axis, a bidirectional framework integrating neural, endocrine, and immune signals. Under chronic stress, sustained overactivation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS), coupled with secondary renin–angiotensin–aldosterone system (RAAS) dysregulation, creates a deleterious intrarenal milieu. Unlike classical models driven by high salt or metabolic disorders, a proposed hallmark of stress-induced injury is the non-classical activation of the mineralocorticoid receptor (MR). Given MR’s equal affinity for cortisol and aldosterone, the protective barrier maintained by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is compromised under persistent glucocorticoid elevation. This may allow cortisol to escape inactivation and aberrantly activate intrarenal MR, a process putatively termed gluco-mineralo cross-activation. This mechanism is hypothesized to initiate profibrotic cascades via NADPH oxidase 4 (NOX4)/ROS/TGF-β/Smad pathways and amplifies the complement C5a-C5a receptor 1 inflammatory axis, culminating in fibrosis and sclerosis. Based on these insights, we propose stress-related kidney disease (SRKD) as a distinct clinical entity. This review synthesizes current evidence to guide precision interventions targeting the brain–kidney axis.