Thickened Perirenal Fat Predicts Poor Renal Outcome in Patients with Immunoglobulin A Nephropathy: A Population-Based Retrospective Cohort Study.

Introduction: Perirenal fat is a pad that fills the retroperitoneal space outside the kidney, which affects kidney function in various ways. However, the association between perirenal fat and IgA nephropathy (IgAN) has not yet been elucidated. This study aimed to investigate the role of perirenal fat in predicting IgAN progression. Methods: A total of 473 patients with biopsy-proven IgAN and follow-up information were recruited, and perirenal fat thickness (PFT) was measured using color Doppler ultrasonography at renal biopsy. Patients were divided into two groups according to the median PFT: the low-PFT group (PFT ≤1.34 cm, n = 239) and the high PFT group (PFT >1.35 cm, n = 234). A total of 473 healthy participants were included in the control group. Basic clinical characteristics were assessed at the time of renal biopsy, and the relationship between PFT and combined endpoints was analyzed. The renal composite endpoints were defined as a two-fold increase in blood creatinine level, end-stage renal disease (dialysis over 3 months). Kaplan-Meier survival analysis was used to explore the role of PFT in the progression of IgAN. Three clinicopathological models of multivariate Cox regression analysis were established to evaluate the association between PFT and renal prognosis in patients with IgAN. Results: Compared to healthy subjects, patients with IgAN showed significantly higher PFT. After a median follow-up of 50 months, 75 of 473 patients (15.9%) with IgAN reached renal composite endpoints. Among those, 13 of 239 patients (5.4%) were in the low PFT group, and 62 of 234 patients (26.5%) were in the high PFT group (p < 0.001). The results of three Cox regression models (including demographics, pathological and clinical indicators, and PFT) demonstrated that a higher PFT was significantly associated with a higher risk of reaching renal composite endpoints in patients with IgAN. Conclusion: This study indicated a positive relationship between PFT at renal biopsy and renal progression in patients with IgAN, suggesting that perirenal fat might act as a marker of poor prognosis in patients with IgAN.

ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment. Video Abstract.

Dihydroxyacetone phosphate accumulation leads to podocyte pyroptosis in diabetic kidney disease.

Diabetic kidney disease (DKD) can lead to accumulation of glucose upstream metabolites due to dysfunctional glycolysis. But the effects of accumulated glycolysis metabolites on podocytes in DKD remain unknown. The present study examined the effect of dihydroxyacetone phosphate (DHAP) on high glucose induced podocyte pyroptosis. By metabolomics, levels of DHAP, GAP, glucose-6-phosphate and fructose 1, 6-bisphosphate were significantly increased in glomeruli of db/db mice. Furthermore, the expression of LDHA and PKM2 were decreased. mRNA sequencing showed upregulation of pyroptosis-related genes (Nlrp3, Casp1, etc.). Targeted metabolomics demonstrated higher level of DHAP in HG-treated podocytes. In vitro, ALDOB expression in HG-treated podocytes was significantly increased. siALDOB-transfected podocytes showed less DHAP level, mTORC1 activation, reactive oxygen species (ROS) production, and pyroptosis, while overexpression of ALDOB had opposite effects. Furthermore, GAP had no effect on mTORC1 activation, and mTORC1 inhibitor rapamycin alleviated ROS production and pyroptosis in HG-stimulated podocytes. Our findings demonstrate that DHAP represents a critical metabolic product for pyroptosis in HG-stimulated podocytes through regulation of mTORC1 pathway. In addition, the results provide evidence that podocyte injury in DKD may be treated by reducing DHAP.

Ion homeostasis in diabetic kidney disease.

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.

LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis.

Alteration of metabolic phenotype in podocytes directly contributes to the development of albuminuria and renal injury in conditions of diabetic kidney disease (DKD). This study aimed to identify and evaluate liver receptor homologue-1 (LRH-1) as a possible therapeutic target that alleviates glutamine (Gln) metabolism disorders and mitigates podocyte injury in DKD. Metabolomic and transcriptomic analyses were performed to characterize amino acid metabolism changes in the glomeruli of diabetic mice. Next, Western blotting, immunohistochemistry assays, and immunofluorescence staining were used to detect the expression of different genes in vitro and in vivo. Furthermore, Gln and glutamate (Glu) content as well as ATP generation were examined. A decrease in LRH-1 and glutaminase 2 (GLS2) expression was detected in diabetic podocytes. Conversely, the administration of LRH-1 agonist (DLPC) upregulated the expression of GLS2 and promoted glutaminolysis, with an improvement in mitochondrial dysfunction and less apoptosis in podocytes compared to those in vehicle-treated db/db mice. Our study indicates the essential role of LRH-1 in governing the Gln metabolism of podocytes, targeting LRH-1 could restore podocytes from diabetes-induced disturbed glutaminolysis in mitochondria.

The Utility of Perirenal Fat in Determining the Risk of Onset and Progression of Diabetic Kidney Disease.

Background: Perirenal fat (PRF) has multiple effects on the kidney through its physical structure and adipocytokine-secreting ability. The present study explored the relationship between PRF thickness and the onset and progression of albuminuria in patients with diabetes. Methods: In the cross-sectional analysis, we screened 959 patients from 8764 subjects with type 2 diabetes mellitus (T2DM) who met the inclusion criteria and measured their perirenal fat thickness (PFT) using color Doppler ultrasound. A group of laboratory indexes were included in the analysis models. In a longitudinal study, a total of 218 patients with a baseline UACR <30 mg/g were included in the follow-up study. Results: In a cross-sectional analysis, patients with diabetes and higher PFT presented with higher albuminuria. Multiple logistic regression analysis indicated that PFT was an independent risk factor for the degree of albuminuria in patients with T2DM (odds ratio = 4.186, 95%CI: 2.290-7.653, P < 0.001). In a longitudinal study, 218 albuminuria-free patients with T2DM at the baseline were followed up for a mean of 12.3 months. Based on the cutoff value from the ROC diagnostic test in the cross-sectional study, patients were divided into two groups: higher PFT (H-PFT) and lower PFT (L-PFT). Kaplan-Meier survival curve analysis showed that H-PFT was associated with a higher incidence of albuminuria than L-PFT (log-rank test, χ2 = 4.522, P = 0.033). Cox regression analysis showed that PFT was a risk factor for the earlier onset of albuminuria (hazard ratio 2.83, 95% CI: 1.34-4.88, P < 0.001). Conclusions: PRF evaluated by color Doppler ultrasound is an easy and reliable tool for predicting the onset and progression of albuminuria in patients with T2DM.

SIRT6 Activator UBCS039 Inhibits Thioacetamide-Induced Hepatic Injury In Vitro and In Vivo.

SIRT6 has been reported to have multiple functions in inflammation and metabolism. In the present study, we explored the regulatory effects and mechanisms of SIRT6 in thioacetamide (TAA)-induced mice acute liver failure (ALF) models. The SIRT6 activator UBCS039 was used in this animal and cell experiments. We observed that UBCS039 ameliorated liver damage, including inflammatory responses and oxidative stress. Further study of mechanisms showed that the upregulation of SIRT6 inhibited the inflammation reaction by suppressing the nuclear factor-κB (NF-κB) pathway in the TAA-induced ALF mice model and lipopolysaccharide-stimulated macrophages. In addition, the upregulation of SIRT6 alleviated oxidative stress damage in hepatocytes by regulating the Nrf2/HO-1 pathway. These findings demonstrate that pharmacologic activator of SIRT6 could be a promising target for ALF.

PFKP Activation Ameliorates Foot Process Fusion in Podocytes in Diabetic Kidney Disease.

Background: Glycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified. Methods: mRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using Pfkp siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed in vitro. The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b (Aldob) siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney. Results: mRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes (Hk1, and Pfkp) and down-regulation of downstream genes of glycolysis (Pkm, and Ldha). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. In vitro, the Pfkp siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB in vitro rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice. Conclusions: These findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.