Large clinical trials and real-world studies have demonstrated that the beneficial effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal outcomes regardless of the presence of diabetes. However, the mechanism remains obscure.Here, we analyze the anti-fibrotic and anti-inflammatory effects of dapagliflozin, a SGLT2 inhibitor, on renal alternations using the ischemia/reperfusioninduced fibrosis model. Transcriptome and metabolome analysis showed that

Mitochondrial dysfunction leads to loss of renal function and structure; however, the precise mechanisms by which mitochondrial function can regulate renal fibrosis remain unclear. Proximal tubular cells (PTCs) prefer fatty acid oxidation as their energy source and dysregulation of lipid metabolism has been linked to tubulointerstitial fibrosis (TIF). Here, we demonstrated that mitochondrial uncoupling protein 2 (UCP2) regulates TIF through the stimulation of lipid deposition and extracellular matrix (ECM) accumulation. We show that UCP2 expression was increased in human biopsy sample and mouse kidney tissues with TIF. Moreover, UCP2-deficient mice displayed mitigated renal fibrosis in I/R-induced mouse model of TIF. Consistent with these results, UCP2 deficiency displayed reduced lipid deposition and ECM accumulation in vivo and in vitro. In UCP2-deficient PTCs, inhibition of TIF resulted from downregulation of hypoxia-inducible factor-1α (HIF-1α), a key regulator of lipid metabolism and ECM accumulation. Furthermore, we describe a molecular mechanism by which UCP2 regulates HIF-1α stabilization through regulation of mitochondrial respiration and tissue hypoxia during TIF. HIF-1α inhibition by siRNA suppressed lipid and ECM accumulation by restoration of PPARα and CPT1α, as well as suppression of fibronectin and collagen I expression in PTCs. In conclusion, our results suggest that UCP2 regulates TIF by inducing the HIF-1α stabilization pathway in tubular cells. These results identify UCP2 as a potential therapeutic target in treating chronic renal fibrosis.

Impaired energy metabolism in proximal tubular epithelial cells (PTECs) is strongly associated with various kidney diseases. Here, we characterized proximal tubular phenotype alternations during kidney injury and repair in a mouse model of folic acid nephropathy, in parallel, identified carnitine palmitoyltransferase 1α (CPT1α) as an energy stress response accompanied by renal tubular dedifferentiation. Genetic ablation of Cpt1α aggravated the tubular injury and interstitial fibrosis and hampered kidney repair indicate that CPT1α is vital for the preservation and recovery of tubular phenotype. Our data showed that the lipid accumulation and mitochondrial mass reduction induced by folic acid were persistent and became progressively more severe in PTECs without CPT1α. Interference of CPT1α reduced capacities of mitochondrial respiration and ATP production in PTECs, and further sensitized cells to folic acid-induced phenotypic changes. On the contrary, overexpression of CPT1α protected mitochondrial respiration and prevented against folic acid-induced tubular cell damage. These findings link CPT1α to intrinsic mechanisms regulating the mitochondrial respiration and phenotype of kidney tubules that may contribute to renal pathology during injury and repair.

As a common muscle relaxant, cisatracurium has shown good antitumor effect on some tumors. Recent studies reported that cisatracurium could inhibit the progression of colon cancer by upregulating tumor suppressor gene p53. However, its role in ovarian cancer and its regulatory effect on p53 and p53 downstream targeting gene long intergenic noncoding RNA p21 (lincRNA-p21) is still unknown. Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) was used to assess the expression of p53, lincRNA-p21 and miR-181b. Cell viability and proliferation were detected by CCK-8 assay and Edu staining, respectively. Wound-healing and Transwell assays were performed to determine the abilities of cell migration and invasion. Apoptosis was evaluated by TUNEL staining. Luciferase reporter assay was conducted to detect the relationship between lincRNA-p21 and miR-181b. As a result, cisatracurium could increase the expressions of p53 and lincRNA-p21 of ovarian cancer cell line (OVCAR-3) in a dose-dependent manner. In addition, cisatracurium significantly inhibited the proliferation, migration and invasion of OVACR-3 cells, and induced apoptosis. However, these above changes in biological function can be attenuated by lincRNA-p21 knockdown. Next, lincRNA-p21 could directly target miR-181b and negatively regulate its expression by luciferase reporter assay. In conclusion, cisatracurium inhibited the progression of OVCAR-3 cells through upregulation of lincRNA-p21 expression activated by p53 inhibiting miR-181b expression. The experimental results provide a new research idea for the application of cisatracurium in ovarian cancer.

ObjectiveDiabetic kidney disease (DKD) has been shown to be associated with an excess risk of cardiovascular death. Inflammation has been considered central to type 2 diabetes (T2D) pathophysiology, and inflammation markers have been linked to cardiovascular disease. The serum and urinary IL-18 levels were significantly elevated in patients with T2D; however, whether interleukin 18 (IL-18) are associated with the severity of arterial stiffness remains to be determined. This study examined the relationship of IL-18 levels with pulse wave velocity (PWV) as a reflector for arterial stiffness in patients with T2D.MethodsA total of 180 participants with T2D who had undergone PWV examination were enrolled. Serum and urinary IL-18 levels were measured using sandwich enzyme linked immunosorbent assay (ELISA) kits. Arterial stiffness was determined by carotid–femoral PWV (cf-PWV) and carotid–radial PWV (cr-PWV).ResultsThe urinary IL-18 levels correlated positively with cf-PWV in patients with T2D with DKD (r = 0.418, p < 0.001); however, we found no significant correlation between urinary IL-18 and cf-PWV in diabetic subjects without DKD. In addition, we found no significant correlation between urinary IL-18 and cr-PWV in participants with T2D with or without DKD. Moreover, the association remained significant when controlling for arterial stiffness risk factors, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. cf-PWV was greater in the higher group of urinary IL-18 than in the lower group. Nevertheless, we found no significant correlation between serum IL-18 and cf-PWV in participants with T2D.ConclusionThe urinary IL-18 levels appear to be associated with greater cf-PWV, suggesting the link between urinary IL-18 and arterial stiffness in patients with T2D.