Loss of Farnesoid X receptor (FXR) accelerates dysregulated glucose and renal injury in db/db mice.

Background: End-stage renal disease is primarily caused by diabetic kidney disease (DKD). The Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has anti-inflammatory, lipid-lowering and hypoglycemic properties. It also inhibits renal fibrosis. Although its physiological role is not fully understood, it also plays a role in the control of diabetic nephropathy (DN). Methods: In the present study, we examined male FXR & leptin receptor double knockout mice, in which weight, blood glucose, body fat, and other indicators were monitored. After 6 months of rearing, blood and urine samples were collected and biochemical parameters were measured. Fibrosis was assessed by Masson's stain, while the assessment of the resuscitation case's condition was performed using succinate dehydrogenase (SDHA) stain immunohistochemistry, which measures aerobic respiration. Expression of molecules such as connective tissue growth factor (CTGF), SMAD family members 3 (Smad3) and 7 (Smad7), and small heterodimer partner were detected by RT-PCR and Western blotting as part of the application. Results: FXR knockout decreased body weight and body fat in db/db mice, but increased blood glucose, urine output, and renal fibrosis. Primary mesangial cells (P-MCs) from FXR+/ + mice stimulated with transforming growth factor ß1 (TGFß1) showed significantly higher levels of related fibrosis factors, TGFß1 and Smad3 mRNA and protein, and significantly reduced levels of Smad7. These effects were reversed by the action of FXR agonist chenodeoxycholic acid (CDCA). P-MCs from FXR-/ - mice stimulated with TGFß1 resulted in an increase in the expression and protein levels of collagen I and TGFß1, and the addition of CDCA had no significant effect on TGFß1 stimulation. However, compared with FXR+/ +db/db mice, the rate of oxygen consumption, the rate of carbon dioxide production, and the rate of energy conversion were increased in FXR-/ -db/db mice, whereas the SDHA succinate dehydrogenase, a marker enzyme for aerobic respiration, was significantly decreased. Conclusions: These results provide evidence that FXR plays a critical role in the regulation of mesangial cells in DN. The likely mechanism is that aberrant FXR expression activates TGFß1, which induces extracellular matrix accumulation through the classical Smad signaling pathway, leading to mitochondrial dysfunction.

Correlations of PCSK9 and LDLR Gene Polymorphisms and Serum PCSK9 Levels With Atherosclerosis and Lipid Metabolism in Patients on Maintenance Hemodialysis.

This study is aimed at investigating the correlations of PCSK9 and LDLR gene polymorphisms as well as serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels with atherosclerosis and lipid metabolism in patients on maintenance hemodialysis (HD). A single nucleotide polymorphism at the E670G locus of the PCSK9 gene and the rs688 locus of the LDLR gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. All study subjects' blood lipid (triglyceride [TG], total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]) concentrations and lipoprotein(a) and PCSK9 levels were measured. The differences in blood lipid levels between different genotypes of the E670G locus of the PCSK9 gene and the rs688 locus of the LDLR gene in patients on maintenance HD with atherosclerosis were compared. Patients on maintenance HD with atherosclerosis at the E670G locus of the PCSK9 gene AG + GG genotype had higher levels of TG, TC, LDL-C, and lipoprotein(a) than the AA genotype, and lower levels of HDL-C than the AA genotype. Patients on maintenance HD with atherosclerosis at the rs688 locus of the LDLR gene CT + TT genotype had higher levels of TG, TC, LDL-C, and lipoprotein(a) than the CC genotype, and lower levels of HDL-C than the CC genotype. Serum PCSK9 contents in patients on maintenance HD with atherosclerosis were positively correlated with lipid indices (TG, TC, LDL-C, and lipoprotein(a)) and carotid ultrasound indices (intima-media thickness and resistance index), and negatively correlated with HDL-C, maximum systolic blood flow velocity, and minimum diastolic blood flow velocity (all P < .05).