Diabetic kidney disease (DKD) is characterized by podocyte injury driven by intracellular lipid accumulation. Liver receptor homolog-1 (LRH-1) is a key nuclear receptor regulating lipid metabolism, yet its role in podocyte lipotoxicity remains unclear. This study identifies the LRH-1/perilipin 5 (PLIN5) axis as a critical pathway for maintaining lipid homeostasis in podocytes and a promising pharmacological target for DKD. We demonstrated that hyperglycemia suppressed the LRH-1/PLIN5 axis, leading to lipid droplet accumulation, oxidative stress, and podocyte injury in db/db mice and cultured podocytes. Activation of LRH-1 with agonist 1,2-dilauroyl-sn-glycerol-3-phosphocholine (DLPC) or its overexpression restored mitochondrial lipid utilization, reduced lysosomal lipotoxicity, and protected against renal injury by upregulating PLIN5. Furthermore, virtual screening of a natural product library identified chebulinic acid (CA) as a novel PLIN5-targeting agonist. CA treatment significantly upregulated PLIN5 expression, ameliorated lipid accumulation, and improved renal function in db/db mice. Our findings unveil the therapeutic potential of targeting the LRH-1/PLIN5 axis and present CA as a promising candidate for the treatment of diabetic podocytopathy.

Chronic kidney disease (CKD) remains a major global health challenge. Angiotensin II (Ang II)-induced lipotoxicity is an important contributor to podocyte injury. Perilipin 5 (PLIN5) is a lipid droplet-associated protein that helps maintain cellular metabolic homeostasis. However, how PLIN5 protects podocytes from lipotoxic stress remains incompletely understood. In this study, we generated podocyte-specific PLIN5 knockout mice using the Cre-loxP system and induced PLIN5 overexpression in vivo and in vitro. We found that Ang II markedly downregulated PLIN5 expression in podocytes both in vivo and in vitro. Podocyte-specific deletion of PLIN5 aggravated Ang II-induced lipid accumulation, mitochondrial dysfunction and apoptosis, whereas PLIN5 overexpression alleviated these abnormalities. Proteomic screening identified FK506-binding protein 8 (FKBP8), an outer mitochondrial membrane protein, as a PLIN5-interacting partner. Co-immunoprecipitation and proximity ligation assays showed that the PLIN5-FKBP8 interaction was reduced under Ang II stimulation. Functionally, FKBP8 knockdown disrupted lipid droplet-mitochondria contact and exacerbated Ang II-induced podocyte lipotoxicity. Domain-mapping and rescue experiments further demonstrated that the 70-200 amino acid region of FKBP8 is required for PLIN5 binding and for preservation of lipid droplet-mitochondria contact under lipotoxic stress. In addition, disruption of the PLIN5-FKBP8 axis was associated with impaired fatty acid utilisation and altered mitochondrial homeostasis. Collectively, these findings support a model in which PLIN5 protects podocytes, at least in part, by interacting with FKBP8 and preserving lipid droplet-mitochondria contact, thereby limiting Ang II-induced lipotoxic injury.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, characterized by tubular epithelial cell (TECs) senescence, inflammation, and fibrosis. This study investigates the role of estrogen-related receptor alpha (ERRα) in regulating TECs senescence in DKD through nitric oxide synthase 2 (NOS2)-mediated citrulline metabolism. We demonstrate that ERRα expression is significantly downregulated in renal tubular cells of both diabetic mice and DKD patients, correlating with increased senescence markers and the senescence-associated secretory phenotype (SASP). Mechanistically, transcriptome and chromatin immunoprecipitation sequencing confirmed that ERRα regulates NOS2 transcription. TECs-specific knockout of ERRα led to reduced NOS2 expression and decreased citrulline levels, exacerbating TECs injury and senescence. In contrast, TECs-specific knock-in of ERRα alleviated TECs injury and senescence and restored citrulline metabolism. These findings indicate that ERRα plays a critical role in regulating NOS2-mediated citrulline metabolism, which is essential for maintaining kidney function and mitigating tubular senescence in DKD. Furthermore, overexpression of NOS2 and supplementation with citrulline ameliorated renal dysfunction and cellular senescence in diabetic mice, underscoring the importance of this metabolic axis. Modulating ERRα and NOS2 activity may present a potential therapeutic strategy to reduce kidney injury and slow the progression of DKD.

Cluster of Differentiation 36 (CD36), also known as scavenger receptor B2, plays a critical role in controlling podocyte lipid metabolism, mediating the onset and progression of diabetic kidney disease (DKD). However, the post-translational regulation of CD36 and its exact role in lipid transport within podocytes remain unclear. In this study, we elucidate the mechanism by which acyl-protein thioesterase 1 (APT1) depalmitoylates CD36 in podocytes. We reveal that APT1 interacts with CD36 and reduces its palmitoylation at Cys466 specifically, thereby promoting its trafficking from the plasma membrane to lysosomes for degradation. Diabetes-induced downregulation of APT1 redirects palmitoylated CD36 into the recycling pathway. Consequently, enhanced lipid uptake in podocytes leads to lipotoxicity. Conversely, APT1 overexpression mitigates lipid accumulation by enhancing lysosomal degradation and reducing plasma membrane-associated CD36. Our findings indicate that diabetes-induced APT1 deficiency promotes palmitoylated CD36 enrichment on plasma membranes through decreased APT1 expression, driving lipid overload and podocyte injury.

Lupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking. To assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis. This prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020. Oral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid. Total remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified). A total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively). This randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis. ClinicalTrials.gov Identifier: NCT02256150

Diabetic kidney disease (DKD) is increasingly recognized as a consequence of impaired mitochondrial quality control in renal tubular epithelial cells (TECs). In this study we show that the nuclear receptor ESRRA (estrogen related receptor alpha) transcriptionally activates ATG5 (autophagy related 5) to sustain PINK1 (PTEN induced kinase 1)-dependent mitophagy and preserve tubular homeostasis. ESRRA and ATG5 expression were markedly reduced in human DKD biopsies, and their abundance correlated positively with estimated glomerular filtration rate and inversely with albuminuria. Conditional deletion of Esrra in mouse tubules or CRISPR-Cas9 knockout in primary TECs suppressed mitophagy, exacerbated mitochondrial dysfunction and aggravated tubulointerstitial fibrosis, whereas tubular Esrra re-expression or Atg5 overexpression restored mitophagy and attenuated renal injury. Multi-omics and mechanistic assays identified the natural polyphenol salvianolic acid C (SAC) as a high-affinity ESRRA agonist that binds Asp326, Phe382 and Ala396, stabilizes the receptor and upregulates ATG5. SAC dose-dependently improved proteinuria, renal function, mitochondrial respiration and insulin sensitivity in db/db and high-fat diet-streptozotocin DKD models without overt toxicity. Metabolomic profiling revealed that ESRRA-ATG5-driven mitophagy targets ARG2 (arginase 2) for autophagy-lysosomal degradation, thereby shifting L-arginine flux from urea production toward nitric-oxide synthesis; exogenous L-arginine partly rescued renal injury in Esrra-deficient mice. Collectively, this study uncovers an ESRRA-ATG5 axis that couples selective mitophagy to L-arginine metabolism as a pivotal defense against DKD, and identifies SAC as a first-in-class, naturally derived ESRRA activator with therapeutic potential.Abbreviations: AAV: adeno-associated virus; ACR: albumin:creatinine ratio; ACTA2: actin alpha 2, smooth muscle; AKI: acute kidney injury; ALB: albumin; ARG2: arginase 2; ATG12: autophagy related 12; ATG16L1: autophagy related 16-like 1; ATG5: autophagy related 5; BafA1: bafilomycin A1; BUN: blood urea nitrogen; CETSA: cellular thermal shift assay; ChIP-qPCR: chromatin immunoprecipitation followed by quantitative PCR; ChIP-Seq: chromatin immunoprecipitation sequencing; Co-IP: co-immunoprecipitation; CON: control; Cr: creatinine; DEGs: differentially expressed genes; DHE: dihydroethidium; DKD: diabetic kidney disease; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; ESRRA: estrogen related receptor alpha; FSGS: focal segmental glomerulosclerosis; GSEA: gene set enrichment analysis; GTT: glucose tolerance test; HE: hematoxylin and eosin; HFD: high-fat diet; HG: high glucose; HOMA-IR: homeostatic model assessment of insulin resistance; IF: immunofluorescence; IgAN: immunoglobulin A nephropathy; IHC: immunohistochemistry; IOD: integrated optical density; ITT: insulin tolerance test; KD: equilibrium dissociation constant; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; LUC: luciferase; MCN: minimal change nephrosis; MST: microscale thermophoresis; MTS: mitochondrial targeting sequence; NAFLD: non-alcoholic fatty liver disease; NIH: National Institutes of Health; NO: nitric oxide; OCR: oxygen consumption rate; PAS: periodic acid-Schiff; PCR: polymerase chain reaction; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: quantitative PCR; RNA-seq: RNA sequencing; ROS: reactive oxygen species; RT-qPCR: reverse transcription quantitative PCR; SAC: salvianolic acid C; SAFI: salvianolic acid for injection; SDH: succinate dehydrogenase; SEM: standard error of the mean; SPF: specific pathogen-free; SPR: surface plasmon resonance; STZ: streptozotocin; TCA: tricarboxylic acid; TECs: tubular epithelial cells; TEM: transmission electron microscopy; TFAM: transcription factor A, mitochondrial.

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases.

Chronic kidney disease (CKD) is a major health issue, with podocyte injury with senescence playing a central role in glomerulosclerosis. This study investigates the link between glycolysis-derived serine metabolism and podocyte injury with senescence, focusing on the role of phosphoglycerate kinase 1 (PGK1) in the regulation of L-serine synthesis and podocyte homeostasis. Using in vivo and in vitro models, we examined the effects of angiotensin II (Ang II)-induced metabolic dysregulation on serine metabolism and its impact on podocyte function. The results demonstrate that Ang II downregulates PGK1 expression through the transcription factor FOXA1, leading to reduced L-serine biosynthesis, mitochondrial dysfunction, and increased cellular senescence in podocytes. Supplementing with L-serine or enhancing PGK1 expression in podocytes alleviated these pathological changes, restored mitochondrial function, and reduced senescence-associated phenotypes in CKD mouse models. Moreover, PGK1 was found to interact with keratin, type II cytoskeletal 1 (KRT1), stabilizing the cytoskeletal integrity of podocytes. These findings identify a novel metabolic pathway linking glycolysis, serine metabolism, and podocyte injury with senescence, suggesting that targeting the PGK1-serine axis may offer therapeutic potential for slowing podocyte senescence and CKD progression.

Background Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear. Methods The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation. Results USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation. Conclusion This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.

Renal interstitial fibrosis is the final common outcome of various chronic kidney diseases (CKD). Renal tubular epithelial cells (TECs) G2/M cell cycle arrest play a pivotal role in renal fibrosis. Although RNA-binding proteins (RBPs) are implicated in organ fibrosis, the underlying mechanisms remain poorly understood. Here, we identify DEAD-box protein 21 (DDX21), a representative RBP, as highly expressed in fibrotic renal tissues, especially in TECs. Moreover, DDX21 expression is positively correlated with renal function decline in CKD patients, underscoring its role in disease progression. TECs-specific deletion of Ddx21 alleviates cell cycle arrest in G2/M, and attenuates fibrotic responses. Mechanistically, silencing DDX21 reduces p21 expression at both the mRNA and protein levels and decreases cell apoptosis, indicating that DDX21 promotes G2/M cell cycle arrest by regulating the p21 signaling pathway. This study suggests that DDX21 may serve as a promising therapeutic target for kidney fibrosis.

Podocytes, highly specialized glomerular epithelial cells, are essential for maintaining the filtration barrier integrity, yet they are particularly susceptible to metabolic stress. Recent advances have identified metabolic reprogramming as a central driver of podocyte injury in diverse glomerular diseases, including diabetic kidney disease and FSGS. Pathologic stimuli, such as hyperglycemia, lipotoxicity, oxidative stress, and inflammatory cytokines, lead to profound alterations in podocyte metabolism, encompassing dysregulation of lipid, glucose, amino acid, and ion handling and activation of immunometabolic pathways. These maladaptive changes result in mitochondrial dysfunction, cytoskeletal disorganization, and inflammatory forms of cell death including pyroptosis and ferroptosis. Mechanistic studies have elucidated the roles of nutrient-sensing pathways (AMP-activated protein kinase, mechanistic target of rapamycin, and sirtuin-1), innate immune sensors (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 and cyclic GMP-AMP synthase-stimulator of IFN genes), and metabolic enzymes (ceramide synthase 6, glutaminase-2, and ornithine decarboxylase-1) in orchestrating this reprogramming. Emerging evidence supports the therapeutic potential of modulating podocyte metabolism, as exemplified by the renoprotective effects of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, and targeted inhibitors of inflammasome or lipid pathways. This review synthesizes recent insights into the structural-metabolic coupling in podocytes, dissects the mechanisms of metabolic derangement in disease contexts, and discusses promising therapeutic strategies aimed at restoring metabolic homeostasis. Understanding the intersection between podocyte metabolism and injury response offers novel avenues for the prevention and treatment of chronic glomerular diseases.

Key PointsDiabetic kidney disease progression was associated with increased Piezo1 expression in podocytes.Specific Piezo1 deletion alleviated podocyte injury in diabetic models.Piezo1 contributes to podocyte injury through nuclear factor of activated T cell cytoplasmic 1-transient receptor potential cation channel 6 signaling.BackgroundDiabetic kidney disease (DKD) is characterized by progressive injury to glomerular podocytes due to sustained mechanical stress within the glomerulus. Piezo proteins, acting as cellular mechanosensors, play a pivotal role in mechanotransduction by sensing mechanical forces and regulating intracellular ion flux. This study investigates the role of Piezo1 in the progression of DKD and its mechanistic involvement in podocyte injury.MethodsPodocyte-specific Piezo1 knockout mice were generated using the streptozotocin plus high-fat diet model of DKD. In vitro studies included the use of Piezo1 inhibitors to assess calcium influx, podocyte cytoskeletal rearrangement, and apoptosis under stiff matrix conditions. In addition, NF of activated T-cell cytoplasmic 1 (NFATc1) and transient receptor potential cation channel 6 (TRPC6) signaling pathways were explored to establish their role in Piezo1-mediated podocyte injury. Adeno-associated virus TRPC6 was used to overexpress TRPC6 in podocyte-specific Piezo1 knockout mice to assess the in vivo interaction between Piezo1 and TRPC6.ResultsPodocyte-specific deletion of Piezo1 significantly ameliorated the progression of DKD in diabetic mice. Inhibition of Piezo1 reduced calcium influx, cytoskeletal rearrangement, and podocyte apoptosis in vitro. Mechanistically, Piezo1 activation triggered a signaling loop involving NFATc1 and TRPC6, leading to increased calcium influx, perpetuating podocyte injury. TRPC6 overexpression in vivo counteracted the protective effects of Piezo1 deletion, confirming the critical role of the Piezo1/NFATc1/TRPC6 axis in DKD progression.ConclusionsPiezo1 plays a key mechanosensory role in podocyte injury during DKD progression by mediating calcium influx and activating the NFATc1/TRPC6 signaling pathway.

Importance:Lupus nephritis is typically treated with intravenous cyclophosphamide, which is associated with serious adverse effects. Oral mizoribine may be an alternative for induction therapy of lupus nephritis. However, large-scale, long-term, randomized clinical studies of mizoribine are lacking. Objective:To assess the efficacy and safety of oral mizoribine vs intravenous cyclophosphamide as induction therapy for Chinese patients with lupus nephritis. Design, Setting, and Participants:This prospective, multicenter, parallel-group, open-label, phase 3 randomized clinical trial recruited patients with class III, III+V, IV, IV+V, or V lupus nephritis aged 18 to 70 years from 40 centers in China. Inclusion criteria included 24-hour urinary protein level of 1.0 g or higher and systemic lupus erythematosus disease activity index of 8 or higher. The first patient was enrolled on November 29, 2014, and the study finished March 14, 2019. The follow-up period was 52 weeks. Data were analyzed from September 4, 2019, to January 21, 2020. Interventions:Oral mizoribine (50 mg, 3 times a day) or cyclophosphamide (6 intravenous doses at 0.5-1.0 g/m2 body surface area, with a maximum dose of 1.0 g/d) for 52 weeks plus oral glucocorticoid. Main Outcomes and Measures:Total remission rate (complete remission rate plus partial remission rate) after 52 weeks (prespecified). Results:A total of 250 patients were randomized, and 243 patients (mean [SD] age, 34.6 [10.7] years, 213 women [87.7%]) were treated (123 patients [50.6%] in the mizoribine group and 120 patients [49.4%] in the cyclophosphamide group). The total remission rate at 52 weeks was 66.1% (76 of 115 patients) in the mizoribine group and 76.8% (86 of 112 patients) in the cyclophosphamide group, and the relative risk ratio (mizoribine vs cyclophosphamide) was 0.861 (95% CI, 0.729-1.016). The lower limit of this 2-sided 95% CI was greater than the noninferiority margin of 0.726, indicating that mizoribine was noninferior to cyclophosphamide. Changes in other immune parameters and kidney function were generally similar between the groups. The incidence of any treatment-related treatment-emergent adverse events was 80.5% (99 of 123 patients) in the mizoribine group and 78.7% (96 of 122 patients) in the cyclophosphamide group, and the most frequent adverse event in both groups was upper respiratory tract infection (41 patients [33.3%] and 37 patients [30.3%], respectively). Conclusions and Relevance:This randomized clinical trial shows that compared with intravenous cyclophosphamide, oral mizoribine was noninferior and well tolerated when used with glucocorticoid for induction therapy of active lupus nephritis. Mizoribine can be used as an alternative to intravenous cyclophosphamide as induction therapy for lupus nephritis. Trial Registration:ClinicalTrials.gov Identifier: NCT02256150.

Diabetic Kidney Disease (DKD) is a common and serious complication of diabetes, particularly Type 2 Diabetes Mellitus (T2DM), which significantly contributes to patient morbidity and mortality. The limitations of traditional treatments like ACE inhibitors and ARBs in managing DKD progression highlight the need for innovative therapeutic strategies. This review examines the impact of various dietary patterns, such as the Mediterranean diet, ketogenic diet, intermittent fasting, DASH diet, and vegetarian diet, on the management of DKD. Evidence suggests these diets can halt the progression of DKD, although further research is needed to confirm their long-term effectiveness and safety. Personalized dietary approaches tailored to individual needs may enhance outcomes for DKD patients.

The complications of type 2 diabetes are a major global public health problem with high incidence and mortality, affecting almost all individuals with diabetes worldwide. Diabetic kidney disease (DKD) is one such primary complication and has become a leading cause of end-stage renal disease in patients with diabetes. Progression from diabetes to DKD is a complex process typically involving multiple mechanisms. Recent remarkable clinical benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in diabetes and DKD highlight the critical impact of renal ion homeostasis on disease progression. This review comprehensively examines the impact of ion homeostasis on the transition from diabetes to DKD, outlining possible therapeutic interventions and addressing the ongoing challenges in this rapidly developing field.

Cardiolipin (CL) plays a critical role in maintaining mitochondrial membrane integrity and overall mitochondrial homeostasis. Recent studies have suggested that mitochondrial damage resulting from abnormal cardiolipin remodelling is associated with the pathogenesis of diabetic kidney disease (DKD). Acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1) was confirmed to be involved in the progression of Parkinson’s disease, diet-induced obesity and other ageing-related diseases by regulating pathological cardiolipin remodelling. Thus, the purpose of this investigation was to determine the role of ALCAT1-mediated CL remodelling in DKD and to explore the potential underlying mechanism. In vivo study, the mitochondrial structure was examined by transmission electron microscopy (TEM). The colocalization of ALCAT1 and synaptopodin was evaluated by double immunolabelling. Western blotting (WB) was performed to assess ALCAT1 expression in glomeruli. Lipidomics analysis was conducted to evaluate the composition of reconstructed cardiolipins. In vitro study, the lipidomics, TEM and WB analyses were similar to those in vivo. Mitochondrial function was evaluated by measuring the mitochondrial membrane potential (MMP) and the production of ATP and ROS. Here, we showed that increased oxidized cardiolipin (ox-CL) and significant mitochondrial damage were accompanied by increased ALCAT1 expression in the glomeruli of patients with DKD. Similar results were found in db/db mouse kidneys and in cultured podocytes stimulated with high glucose (HG). ALCAT1 deficiency effectively prevented HG-induced ox-CL production and mitochondrial damage in podocytes. In contrast, ALCAT1 upregulation enhanced ox-CL levels and podocyte mitochondrial dysfunction. Moreover, treatment with the cardiolipin antioxidant SS-31 markedly inhibited mitochondrial dysfunction and cell injury, and SS-31 treatment partly reversed the damage mediated by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy through the AMPK pathway. Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment.

As one of the most common primary glomerulopathies, immunoglobulin A nephropathy（IgAN） is a major cause of end-stage renal disease （ESRD）. Its proper treatment has remained rather challenging. Disease progression may be delayed if associated risk factors are intervened. Hyperuricemia is a common clinical feature of IgAN and it is correlated with disease progression. However, the relationship has been elusive between hyperuricemia, pathological injury and disease progression in IgAN. This review focused upon the prevalence of hyperuricemia in IgAN, related pathogenesis and the relationship with the progression of IgAN and therapeutic targets.

Ongoing therapeutic advances in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have significantly reduced the risk of death in AAV, but 30%-50% of patients still relapse. Relapse is a major problem in these diseases, leading to increased morbidity and mortality. It is, therefore, necessary to find predictors of relapse at the end of the remission induction and maintenance phases in order to personalize treatment.

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism-rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis-related genes following FOXK1 protein activation contributes to the energy-related metabolic shift. Nuclear-translocated FOXK1 forms condensate through liquid-liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, the mechanism of a FOXK1-mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.