GDF15 Interference Regulates Proliferation, Inflammation, and Autophagy of Lipopolysaccharide-induced Mesangial Cells by Inhibiting PI3K/ AKT/mTOR Signaling.

BACKGROUND: Chronic glomerulonephritis (CGN) is a primary glomerular disease. As a circulating protein, growth and differentiation factor 15 (GDF15) participates in a variety of biological processes. OBJECTIVE: We aimed to investigate the role of GDF15 in CGN. METHODS: HBZY-1 cells were induced by lipopolysaccharide (LPS). Cell viability was detected using a cell counting kit-8 (CCK-8) assay, and a western blot was applied for the detection of GDF15 protein expression. After GDF15 silencing, cell proliferation was evaluated by CCK-8 assay and 5-ethynyl-2'-deoxyuridine (EDU) staining. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the levels of inflammatory cytokines. Autophagy was assessed by GFP-LC3B assay. Besides, the expression of NF-κB signaling-, autophagy- (LC3II/I, Beclin l and p62) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling-related proteins were measured by western blot. Afterwards, PI3K agonist 740Y-P was used to clarify whether GDF15 affected LPS-induced HBZY-1 cells via PI3K/AKT/mTOR signaling. RESULTS: LPS induction increased cell viability and elevated GDF15 expression in HBZY-1 cells. After GDF15 expression depletion, the increased proliferation of LPS-induced HBZY-1 cells was decreased. Additionally, GDF15 knockdown suppressed the release of inflammatory factors in LPS-induced HBZY-1 cells and activated autophagy. Moreover, the PI3K/AKT/ mTOR signal was evidenced to be activated by GDF15 deficiency. The further addition of 740Y-P reversed the impacts of GDF15 deficiency on the proliferation, inflammation, and autophagy of LPS-induced HBZY-1 Conclusion: Collectively, GDF15 downregulation could protect against CGN via blocking PI3K/AKT/mTOR signaling.

High salt-diet reduces SLC14A1 gene expression in the choroid plexus of Dahl salt sensitive rats.

Elevated Na(+) concentration ([Na(+)]) in the cerebrospinal fluid (CSF) contributes to the development of salt-sensitive hypertension. CSF is formed by the choroid plexus (CP) in cerebral ventricles, and [Na(+)] in CSF is controlled by transporters in CP. Here, we examined the effect of high salt diet on the expression of urea transporters (UTs) in the CP of Dahl S vs Dahl R rats using real time PCR. High salt intake (8%, for 2 weeks) did not alter the mRNA levels of UT-A (encoded by SLC14A2 gene) in the CP of either Dahl S or Dahl R rats. In contrast, the mRNA levels of UT-B (encoded by SLC14A1 gene) were significantly reduced in the CP of Dahl S rats on high salt diet as compared with Dahl R rats or Dahl S rats on normal salt diet. Reduced UT-B expression was associated with increased [Na(+)] in the CSF and elevated mean arterial pressure (MAP) in Dahl S rats treated with high salt diet, as measured by radiotelemetry. High salt diet-induced reduction in UT-B protein expression in the CP of Dahl S rats was confirmed by Western blot. Immunohistochemistry using UT-B specific antibodies demonstrated that UT-B protein was expressed on the epithelial cells in the CP. These data indicate that high salt diet induces elevations in CSF [Na(+)] and in MAP, both of which are associated with reduced UT-B expression in the CP of Dahl S rats, as compared with Dahl R rats. The results suggest that altered UT-B expression in the CP may contribute to an imbalance of water and electrolytes in the CSF of Dahl S rats on high salt diet, thereby leading to alterations in MAP.

HDAC9 gene is associated with stroke risk in a Chinese population.

A recent Genome-Wide Association study (GWAS) identified rs11984041 on HDAC9 gene to be significantly associated with stroke in a Caucasian population. However, whether HDAC9 gene also plays a role in other ethnicities is unknown. The current study was conducted to investigate the association of single nucleotide polymorphisms (SNPs) on HDAC9 gene and stroke risk in a Chinese population. Sixteen tagging SNPs for HDAC9 gene were genotyped in a Chinese population of 279 stroke cases and 984 controls from Changhai Hospital in Shanghai, China. The candidate region of HDAC9 investigated was on a haplotype block located between two recombination hotspots in the tail region of HDAC9, the only region harbouring significantly associated SNPs based on the previous GWAS. rs11984041 was not polymorphic in Chinese population. Two other SNPs, rs2389995 and rs2240419 on HDAC9 of chromosome 7q21.1, were significantly associated with large-vessel stroke risk, with P values of 0.035 and 0.042, respectively (Table 3). Individuals with risk allele (A) for rs2389995 and (T) for rs2240419 had increased risk of stroke (odds ratio [OR] = 1.33, 95% confidence interval [CI]: 1.01-1.75; and OR = 1.29, 95% CI: 1.02-1.63), respectively. Multivariate analysis including both SNPs in the logistic regression model revealed independent association effects of each SNP, with a P = 0.013 and 0.010, respectively. The results from our studies indicate HDAC9 gene is significantly associated with large-vessel stroke risk in Chinese population. However, SNPs on HDAC9 gene display heterogeneity effects across different ethnic populations. Additional studies are needed to further evaluate our results.

Effects of CYP2C19 variant alleles on postclopidogrel platelet reactivity and clinical outcomes in an actual clinical setting in China.

Whether the current pharmacogenetic knowledge of clopidogrel could be translated into Chinese clinical practice is yet to be defined. To address this issue, we assessed the relation of single nucleotide polymorphisms within genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP2B6, CYP2D6, CYP3A4, CYP2C9, and CYP2C19), and biologic activity (P2RY12) to the response of clopidogrel as measured by ex-vivo platelet reactivity and ischemic events during half a year of follow-up. Only CYP2C19*2 and *3, of the investigated polymorphisms, were associated with postclopidogrel platelet aggregation and the presence of high platelet reactivity. Moreover, the effect of the CYP2C19*2 versus the *3 allele on platelet reactivity did not differ. Although the carriage of one or two CYP2C19 loss-of-function alleles, irrespective of the CYP2C19*2 or *3 allele, increased the propensity for high platelet reactivity, only the two loss-of-function allele carriage was associated with clinical outcome in the first 6 months.