Mitochondrial oxidative damage reprograms lipid metabolism of renal tubular epithelial cells in the diabetic kidney.

The functional and structural changes in the proximal tubule play an important role in the occurrence and development of diabetic kidney disease (DKD). Diabetes-induced metabolic changes, including lipid metabolism reprogramming, are reported to lead to changes in the state of tubular epithelial cells (TECs), and among all the disturbances in metabolism, mitochondria serve as central regulators. Mitochondrial dysfunction, accompanied by increased production of mitochondrial reactive oxygen species (mtROS), is considered one of the primary factors causing diabetic tubular injury. Most studies have discussed how altered metabolic flux drives mitochondrial oxidative stress during DKD. In the present study, we focused on targeting mitochondrial damage as an upstream factor in metabolic abnormalities under diabetic conditions in TECs. Using SS31, a tetrapeptide that protects the mitochondrial cristae structure, we demonstrated that mitochondrial oxidative damage contributes to TEC injury and lipid peroxidation caused by lipid accumulation. Mitochondria protected using SS31 significantly reversed the decreased expression of key enzymes and regulators of fatty acid oxidation (FAO), but had no obvious effect on major glucose metabolic rate-limiting enzymes. Mitochondrial oxidative stress facilitated renal Sphingosine-1-phosphate (S1P) deposition and SS31 limited the elevated Acer1, S1pr1 and SPHK1 activity, and the decreased Spns2 expression. These data suggest a role of mitochondrial oxidative damage in unbalanced lipid metabolism, including lipid droplet (LD) formulation, lipid peroxidation, and impaired FAO and sphingolipid homeostasis in DKD. An in vitro study demonstrated that high glucose drove elevated expression of cytosolic phospholipase A2 (cPLA2), which, in turn, was responsible for the altered lipid metabolism, including LD generation and S1P accumulation, in HK-2 cells. A mitochondria-targeted antioxidant inhibited the activation of cPLA2f isoforms. Taken together, these findings identify mechanistic links between mitochondrial oxidative metabolism and reprogrammed lipid metabolism in diabetic TECs, and provide further evidence for the nephroprotective effects of SS31 via influencing metabolic pathways.

CD36 deletion ameliorates diabetic kidney disease by restoring fatty acid oxidation and improving mitochondrial function.

Renal tubular epithelial cells (TECs) are vulnerable to mitochondrial dysregulation, which is an integral part of diabetic kidney disease (DKD). We found that CD36 knockout ameliorated mitochondrial dysfunction and diabetic kidney injury in mice, improved renal function, glomerular hypertrophy, tubular injury, tubulointerstitial fibrosis, and kidney cell apoptosis. Furthermore, CD36 knockout conferred protection against diabetes-induced mitochondrial dysfunction and restored renal tubular cells and mitochondrial morphology. CD36 knockout also restored mitochondrial fatty acid oxidation (FAO) and enhanced FAO-associated respiration in diabetic TECs. CD36 was found to alter cellular metabolic pathways in diabetic kidneys partly via PDK4 the -AMPK axis inactivation. Because CD36 protects against DKD by improving mitochondrial function and restoring FAO, it can serve as a potential therapeutic target.

Berberine ameliorates renal interstitial inflammation and fibrosis in mice with unilateral ureteral obstruction.

Berberine acts via multiple pathways to alleviate fibrosis in various tissues and shows renoprotective effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. Herein, we aimed to investigate the protective effects and molecular mechanisms of berberine against unilateral ureteric obstruction-induced renal fibrosis. The results indicated that berberine treatment (50 mg/kg/day) markedly alleviated histopathological alterations, collagen deposition and inflammatory cell infiltration in kidney tissue and restored mouse renal function. Mechanistically, berberine intervention inhibited NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and the levels of the inflammatory cytokine IL-1ß in the kidneys of unilateral ureteric obstruction mice. In addition, berberine relieved unilateral ureteric obstruction-induced renal injury by activating adenosine monophosphate-activated protein kinase (AMPK) signalling and promoting fatty acid ß-oxidation. In vitro models showed that berberine treatment prevented the TGF-ß1-induced profibrotic phenotype of hexokinase 2 (HK-2) cells, characterized by loss of an epithelial phenotype (alpha smooth muscle actin [α-SMA]) and acquisition of mesenchymal marker expression (E-cadherin), by restoring abnormal fatty acid ß-oxidation and upregulating the expression of the fatty acid ß-oxidation related-key enzymes or regulators (phosphorylated-AMPK, peroxisome proliferator activated receptor alpha [PPARα] and carnitine palmitoyltransferase 1A [CPT1A]). Collectively, berberine alleviated renal fibrosis by inhibiting NLRP3 inflammasome activation and protected tubular epithelial cells by reversing defective fatty acid ß-oxidation. Our findings might be exploited clinically to provide a potential novel therapeutic strategy for renal fibrosis.

Triglyceride-Glucose Index is Significantly Associated with the Risk of Hyperuricemia in Patients with Nonalcoholic Fatty Liver Disease.

Purpose: The triglyceride-glucose (TyG) index is a new index of insulin resistance (IR), and its association with hyperuricemia (HUA) is unclear. The aim of this study was to investigate whether TyG is an independent risk factor for hyperuricemia (HUA) in patients with nonalcoholic fatty liver disease (NAFLD). Patients and Methods: We retrospectively analyzed 461 patients with ultrasound-confirmed NAFLD and calculated the TyG index. Multivariate logistic regression was used to analyze the relationship between the TyG index and HUA in NAFLD patients. The correlation between the TyG index and HUA was further confirmed by a restricted cubic spline. Furthermore, the stability of the association between TyG index and HUA was examined using subgroup analysis. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive value of the TyG index on HUA. Multivariate linear regression was used to analyze the linear relationship between the TyG index and serum uric acid. Results: A total of 166 HUA patients and 295 non-HUA patients were included in the study. The results of multivariate logistic regression analysis showed that after controlling the confounding risk factors, TyG was still an independent risk factor for HUA (OR = 2.00, 95% CI: 1.38 -2.91, p < 0.001). Restricted cubic splines showed that HUA risk increased linearly with TyG across the entire TyG range. The ROC curve showed that TyG index was better than triglyceride in predicting HUA in NAFLD patients, with AUC values of 0.62 and 0.59, respectively. Multiple linear regression analysis showed that TyG index was significantly positively correlated with blood uric acid (B = 1.37, 95% CI: 0.67-2.08, p < 0.001). Conclusion: TyG index is an independent risk factor for HUA in patients with NAFLD. The increase of the TyG index level is closely related to the occurrence and development of HUA in patients with NAFLD.