Ferroptosis is a mechanism of programmed cell death that is characterized by iron-dependent lipid peroxidation, and it is closely associated with organismal metabolism. Modulating ferroptosis may offer therapeutic potential for various diseases. Podocytes are essential intrinsic cells in the renal corpuscle, and podocyte injury contributes to the progression of kidney diseases. A growing number of studies have confirmed that ferroptosis can occur in podocytes, and inhibiting podocyte ferroptosis may provide protective effects in multiple kidney diseases. However, the specific pathogenic molecular mechanisms and treatments for podocyte ferroptosis are still under investigation. In this review, we systematically review the core mechanisms of ferroptosis, including iron metabolism, lipid metabolism, and amino acid metabolism; summarize the molecular mechanisms of podocyte ferroptosis in various types of kidney disease; and discuss the current therapeutic strategies targeting podocyte ferroptosis. By synthesizing this information, we explore the potential of podocyte ferroptosis as a therapeutic target for kidney diseases, aiming to provide insights for both basic research and the clinical treatment of podocyte injury.

Light chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains (LCs) within the proximal tubular epithelial cells, and which is usually classified into crystalline and non-crystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Herein, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ-LCs restricted) and antigen undetermined-MN in a male patient. The patient presented with low molecular weight proteinuria (LMWP), increased serum creatinine levels, and incomplete Fanconi syndrome (FS). To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens which may enrich our recognition of monoclonal gammopathy of renal significance (MGRS) with synchronous MN.Light chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains (LCs) within the proximal tubular epithelial cells, and which is usually classified into crystalline and non-crystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Herein, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ-LCs restricted) and antigen undetermined-MN in a male patient. The patient presented with low molecular weight proteinuria (LMWP), increased serum creatinine levels, and incomplete Fanconi syndrome (FS). To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens which may enrich our recognition of monoclonal gammopathy of renal significance (MGRS) with synchronous MN.

Mixed lineage leukemia 1 (MLL1), a histone H3 lysine 4 (H3K4) methyltransferase, exerts its enzymatic activity by interacting with menin and other proteins. It is unclear whether inhibition of the MLL1-menin interaction influences epithelial-mesenchymal transition (EMT), renal fibroblast activation, and renal fibrosis. In this study, we investigated the effect of disrupting MLL1-menin interaction on those events and mechanisms involved in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), in cultured mouse proximal tubular cells and renal interstitial fibroblasts. Injury to the kidney increased the expression of MLL1 and menin and H3K4 monomethylation (H3K4me1); MLL1 and menin were expressed in renal epithelial cells and renal interstitial fibroblasts. Inhibition of the MLL1-menin interaction by MI-503 administration or siRNA-mediated silencing of MLL1 attenuated UUO-induced renal fibrosis, and reduced expression of α-smooth muscle actin (α-SMA) and fibronectin. These treatments also inhibited UUO-induced expression of transcription factors Snail and Twist and transforming growth factor β1 (TGF-β1) while expression of E-cadherin was preserved. Moreover, treatment with MI-503 and transfection with either MLL siRNA or menin siRNA inhibited TGF-β1-induced upregulation of α-SMA, fibronectin and Snail, phosphorylation of Smad3 and AKT, and downregulation of E-cadherin in cultured renal epithelial cells. Finally, MI-503 was effective in abrogating serum or TGFβ1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1-menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus and is one of the leading causes of end-stage kidney disease. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that play important roles in various diseases, yet their roles in DKD are poorly understood. CircRNA HIPK3 (circHIPK3), a highly conserved circRNA, is closely related to various cellular functions, including cell proliferation and apoptosis. The association between circHIPK3 and diabetic complications has been well demonstrated in multiple previous studies. However, the role of circHIPK3 in podocyte injury in DKD remains unclear. Herein, we discovered that circHIPK3 expression is markedly elevated in cultured podocytes under high-glucose (HG) conditions and glomeruli of diabetic mice, which is closely associated with podocyte injury in DKD. Functionally, lentivirus-mediated knockdown of circHIPK3 dramatically suppresses HG-induced podocyte apoptosis in vitro. Therapeutically, silencing circHIPK3 by adeno-associated virus-mediated RNA interference ameliorates podocyte injury and albuminuria in STZ-induced diabetic mice. Mechanistically, circHIPK3 facilitates the enrichment of fused in sarcoma (FUS) on the ectodysplasin A2 receptor (EDA2R) promoter, resulting in the upregulation of EDA2R expression and activation of apoptotic signaling. Taken together, these results indicate circHIPK3/FUS/EDA2R axis as a therapeutic target for podocyte injury and DKD progression.

Mixed lineage leukemia 1 (MLL1) is a histone H3 lysine 4 (H3K4) methyltransferase that interacts with WD repeat domain 5 (WDR5) to regulate cell survival, proliferation, and senescence. The role of MLL1 in the pathogenesis of acute kidney injury (AKI) is unknown. In this study, we demonstrate that MLL1, WDR5, and trimethylated H3K4 (H3K4me3) were upregulated in renal tubular cells of cisplatin-induced AKI in mice, along with increased phosphorylation of p53 and decreased expression of E-cadherin. Administration of MM102, a selective MLL1/WDR5 complex inhibitor, improved renal function and attenuated tubular injury and apoptosis, while repressing MLL1, WDR5, and H3K4me3, dephosphorylating p53 and preserving E-cadherin. In cultured mouse renal proximal tubular cells (RPTCs) exposed to cisplatin, treatment with MM102 or transfection with siRNAs for either MLL1 or WDR5 also inhibited apoptosis and p53 phosphorylation while preserving E-cadherin expression; p53 inhibition with Pifithrin-α lowered cisplatin-induced apoptosis without affecting expression of MLL1, WDR5, and H3K4me3. Interestingly, silencing of E-cadherin offset MM102's cytoprotective effects, but had no effect on p53 phosphorylation. These findings suggest that MLL1/WDR5 activates p53, which, in turn, represses E-cadherin, leading to apoptosis during cisplatin-induced AKI. Further studies showed that MM102 effectively inhibited cisplatin-triggered DNA damage response (DDR), as indicated by dephosphorylation of ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) proteins, dephosphorylation of checkpoint kinase 1 and 2 (Chk1 and Chk2); depression of γ-H2AX; and restrained cell cycle arrest, as evidenced by decreased expression of p21 and phospho-histone H3 at serine 10 in vitro and in vivo. Overall, we identify MLL1 as a novel DDR regulator that drives cisplatin-induced RPTC apoptosis and AKI by modulating the MLL1/WDR5-/ATR/ATM-Chk-p53-E-cadherin axis. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of AKI.

SET and MYND domain protein 2 (SMYD2) is a lysine methyltransferase that mediates histone H3 lysine 36 trimethylation (H3K36me3) and acts as a regulator of tumorgenesis and cystic growth. However, its role in renal fibrosis remains unknown. In this study, we found that SMYD2 was highly expressed in the murine kidney of renal fibrosis induced by unilateral ureteral obstruction, and primarily located in interstitial fibroblasts and renal tubular epithelial cells. Pharmacological inhibition of SMYD2 with AZ505, a highly selective inhibitor of SMYD2, protected against renal fibrosis and inhibited activation/proliferation of renal interstitial fibroblasts and conversion of epithelial cells to a profibrotic phenotype in this model. In cultured renal interstitial fibroblasts, treatment with AZ505 or silencing of SMYD2 by specific siRNA also inhibited serum- or TGF-β1-induced activation and proliferation of renal interstitial fibroblasts. Mechanistic studies showed that SMYD2 inhibition reduced phosphorylation of several profibrotic signaling molecules, including Smad3, extracellular signal-regulated kinase 1/2, AKT, signal transducer and activator of transcription-3 and nuclear factor-κB in both injured kidney and cultured renal fibroblasts. AZ505 was also effective in suppressing renal expression of Snail and Twist, two transcriptional factors that mediate renal partial epithelial-mesenchymal transition and fibrosis. Conversely, AZ505 treatment prevented downregulation of Smad7, a renoprotective factor in vivo and in vitro. These results indicate that SMYD2 plays a critical role in mediating conversion of epithelial cells to a profibrotic phenotype, renal fibroblast activation and renal fibrogenesis, and suggest that SMYD2 may be a potential target for the treatment of chronic fibrosis in kidney disease.

The methylation of arginine residues by protein arginine methyltransferases (PRMTs) is a crucial post-translational modification for many biological processes, including DNA repair, RNA processing, and transduction of intra- and extracellular signaling. Previous studies have reported that PRMTs are extensively involved in various pathologic states, including cancer, inflammation, and oxidative stress reaction. However, the role of PRMTs has not been well described in kidney diseases. Recent studies have shown that aberrant function of PRMTs and its metabolic products—symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA)—are involved in several renal pathological processes, including renal fibrosis, acute kidney injury (AKI), diabetic nephropathy (DN), hypertension, graft rejection and renal tumors. We aim in this review to elucidate the possible roles of PRMTs in normal renal function and various kidney diseases.

Objective:To explore the clinicopathologic features and risk factors of IgA nephropathy (IgAN) after kidney transplantation.Methods:A retrospective analysis was conducted for biopsy-confirmed IgAN patients after transplantation from January 2016 to September 2019. The clinicopathological characteristics and risk factors of IgAN after expanded criteria donor (ECD) donor for kidney transplantation were examined by statistical analysis of general clinical data and Oxford classification during and after transplantation.Results:The diagnostic rate of IgAN after transplantation was around 12.77%. The clinical symptoms occurred at an average of 22.5 months after transplantation. 66.67%(12/18) patients were in stage 3-4 chronic kidney disease (CKD). There were microscopic hematuria (76.92%) and varying degrees of proteinuria (88.89%). The scores of pathological parameters were as follows: 78% patients with mesangial cell proliferation (M1), 17% with endothelial cell proliferation (E1), 65% with segmental sclerosis (S1), 39% with moderate-to-severe tubules atrophy/interstitial fibrosis (T1/T2) and 17% with crescent formation (C1) respectively. Tubuloatrophy/interstitial fibrosis was associated with estimated glomerular filtration rate (eGFR) at biopsy ( P<0.05). Group of urine protein quantification >1g/d and group of <1g/d group had statistically significant differences in segmental sclerosis and adhesion lesion ( P<0.05). Conclusions:Oxford classification is valuable in the clinical evaluations of allograft IgAN: Tubular atrophy/interstitial fibrosis is associated with a decline of glomerular filtration. And segmental sclerosis and adhesion lesion are correlated with the severity of proteinuria.

Previously, selenoprotein T (SelT) expression was shown to be induced in nervous, endocrine, and metabolic tissues during ontogenetic and regenerative processes. However, whether SelT plays a critical role in renal diseases remains unclear. Here, we explored the role of SelT in cisplatin-induced acute kidney injury (AKI). Results revealed that SelT was highly expressed in renal tubules, but its expression was significantly reduced in cisplatin-induced AKI. Importantly, knocking down of SelT expression in kidney cells in vitro resulted in cisplatin-induced cell apoptosis, as indicated by the elevation of cleaved-PARP and Bax expression, Caspase-3 activity, and number of TUNEL-positive cells. Moreover, SelT silencing-induced reactive oxygen species (ROS) production, accompanied by a decrease in intracellular superoxide dismutase (SOD) and catalase (CAT) activity and increase in malondialdehyde (MDA) content. Notably, the protein and mRNA levels of Nox4 were increased in response to SelT downregulation. Furthermore, suppression of Nox4 expression by GKT137831 partially alleviated SelT knockdown-induced ROS generation and cell apoptosis in cisplatin-treated kidney cells. Taken together, our findings provide the first evidence that SelT protects against cisplatin-induced AKI by suppression of oxidative stress and apoptosis.

It has been accepted that kidney function is connected with brain activity. In clinical studies, chronic kidney disease (CKD) patients have been found to be prone to suffering cognitive decline and Alzheimer’s disease (AD). The cognitive function of CKD patients may improve after kidney transplantation. All these indicators show a possible link between kidney function and dementia. However, little is known about the mechanism behind the relation of CKD and AD. This review discusses the associations between CKD and AD from the perspective of the pathophysiology of the kidney and complications and/or concomitants of CKD that may lead to cognitive decline in the progression of CKD and AD. Potential preventive and therapeutic strategies for AD are also presented. Further studies are warranted in order to confirm whether the setting of CKD is a possible new determinant for cognitive impairment in AD.

Background: Antibody-mediated rejection (ABMR) following kidney transplant is closely associated with poor prognosis of the recipients. Long-lived plasma cells (LLPCs) produce alloantibodies as long as life time and play a crucial role in ABMR. Summary: LLPCs generate from germinal centers and reside in survival niches in the bone marrow as well as the inflamed tissues. They are the main and long-term source of the antibodies. LLPCs mediate ABMR via the generation of preformed antibodies in sensitized patients and de novo antibodies after transplantation. They have been acknowledged as the leading causes of ABMR; however, LLPCs are insensitive to traditional immunosuppressive therapy that removes B cells. Strategies targeting LLPCs, such as antithymocyte globulin, proteasome inhibitors as well as monoclonal antibodies, are promising methods to persistently and thoroughly clear the entire PC pool. Key Message: LLPCs play an important role in ABMR by producing alloantibodies continually, and targeting LLPCs might be a novel and effective approach against ABMR.

The disturbance of podocyte motility is an essential pathogenic mechanisms of foot process effacement during proteinuric diseases, and myosin light chain (MLC) is a pivotal component in regulating the motility of podocytes. Inflammatory cytokine interleukin‐6 (IL‐6) has been reported to induce podocyte abnormalities by various mechanisms, however, whether aberrant cell motility contributes to the IL‐6‐induced podocyte injury remains unknown. Here, by wound healing, transwell, and cell migration assays, we confirmed that IL‐6 accelerates the motility of podocyte. Simultaneously, the phosphorylation of MLC is elevated along with perturbed focal adhesion (FAs) and cytoskeleton. Next, via genetic and pharmacologic interruption of MLC or its phosphorylation we revealed that the activation of MLC is implicated in IL‐6‐mediated podocyte hypermotility as well as the disassembly of FAs and F‐actin. By using stattic, an inhibitor for STAT3 phosphorylation, we uncovered that STAT3 activation is the upstream event for MLC phosphorylation and the following aberrant motility of podocytes. Additionally, we found that calcitriol markedly attenuates podocyte hypermotility via blocking STAT3‐MLC. In conclusion, our study demonstrated that IL‐6 interrupts FAs dynamic, cytoskeleton organization, and eventually leads to podocyte hypermotility via STAT3/MLC, whereas calcitriol exerts its protective role by inhibiting this pathway. These findings enrich the mechanisms accounting for IL‐6‐mediated podocyte injury from the standpoint of cell motility and provide a novel therapeutic target for podocyte disorders.

Significance: The relationship between lipid disturbances and renal diseases has been studied for several decades, and it is well recognized that when the balance of renal lipid uptake, synthesis, oxidation, and outflow is disrupted, lipids will undergo oxidation, be sequestrated as lipid droplets, generate toxic metabolites, and cause nephrotoxicity in diverse renal diseases. Recent Advances: During renal disorders, redox signaling is a pivotal event promoting or resulting from lipid disorders. Accordingly, a vicious cycle of lipid redox dysregulation could be developed, accelerating the renal damage. Critical Issues: The aim of this concise review is to introduce the connection among redox, lipid abnormalities and kidney damage in various conditions. And we summarized current understanding of the lipid redox loop implicated in acute kidney injury, chronic kidney disease, metabolic abnormalities, aging, and genetic pitfalls. Future Directions: Despite recent advances, further investigations are required to clarify the complicated molecular and regulatory mechanisms among redox, lipid mediators and renal disorders. Moreover, exploring an ideal target for potential therapies should be discussed and studied in future.

Background/Aims: Psychological complications are prevalent in patients with chronic kidney disease (CKD). This study aimed to investigate mental disorders in stage 4-5 CKD patients, to detect metabolite concentrations in the brain by proton magnetic resonance spectroscopy (1H-MRS) and to compare the effects of different dialysis therapies on mental disorders in end-stage renal disease (ESRD). Methods: The sample population was made up of predialysis (13), hemodialysis (HD) (13), and peritoneal dialysis (PD) patients (12). We collected the baseline data of patients’ age, sex, hemoglobin (Hb) and parathyroid hormone（PTH） levels. The predialysis patients served as the control group. The psychological status of the three groups was assessed using three psychological scales. 1H-MRS was used to evaluate the relative metabolite concentrations in the bilateral amygdala, hippocampus and unilateral anterior cingulated cortex (ACC). Results: The psychological status was better in HD patients than in predialysis and PD patients. 1H-MRS alterations were predominantly found in the ACC. Choline-containing compounds relative to creatine (Cho/Cr), myo-inositol relative to creatine (MI/Cr) and glutamate and glutamine relative to creatine (Glx/Cr) in the ACC were higher in HD patients. 1H-MRS results were correlated with the baseline data and the scores of psychological scales. Conclusions: CKD patients showed different types of mental disorders as well as metabolite disturbances in the brain. The metabolite concentrations correlated with the psychological status which was better in HD than in predialytic and PD patients.

Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation. Unexpectedly, Nutlin-3a, a MDM2-p53 interaction blocker, had no benefit in protecting diabetic mice from renal impairment in vivo and in alleviating high glucose-induced ECM accumulation in vitro. Intriguingly, we found that Notch1 signaling activation was obviously attenuated by MDM2 depletion in GMCs with high glucose exposure. However, Numb, a substrate of MDM2 which suppresses Notch1 signaling, was found not to be involved in the MDM2 and Notch1 association. Moreover, our findings demonstrated that MDM2 interacted with Notch1 intracellular domain (NICD1) independent of Numb and regulated the ubiquitination status of NICD1. Collectively, our data propose a pivotal role of MDM2 in high glucose-induced GMC proliferation and ECM accumulation, via modulating the activation of Notch1 signaling pathway in an ubiquitination-dependent way.