Bo Wang

Acute kidney injury (AKI) is a serious clinical complication with high morbidity and mortality rates. Despite substantial progress in understanding the mechanism of AKI, no effective therapy is available for treatment or prevention. We previously found that G protein-coupled receptor (GPCR) family member free fatty acid receptor 4 (FFAR4) agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI mice. However, the versatile role of FFAR4 in kidney has not been well characterized. In the study, the expression of FFAR4 was abnormally decreased in tubular epithelial cells (TECs) of cisplatin, cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice, respectively. Systemic and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage, whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI mice. Notably, FFAR4, as a key determinant, was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs, which was indicated by senescence-associated β-galactosidase (SA-β-gal) activity, marker protein p53, p21, Lamin B1, phospho-histone H2A.X, phospho-Rb expression, and secretory phenotype IL-6 level. Mechanistically, pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein, where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and TECs. These findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

BACKGROUND: We aimed to assess the safety and efficiency of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor in combinations with insulin for type 1 and type 2 diabetes mellitus (T1DM and T2DM). METHODS: We searched Medline, Pubmed, Embase, and the Cochrane Collaboration Library from January 2010 to December 2016 without restriction of language. FDA data and Clinical Trials (http://www.clinicaltrials.gov) were also searched. Study selection, data extraction, and evaluation of risk of bias were performed by 2 persons independently. The risk of bias was assessed by Cochrance System Evaluate Method and Q test was used to evaluate the heterogeneity between studies. We used random effect model to analyze the results by Revman 5.3. This meta-analysis has been registered at online public registry PROSPERO (registration number is: CRD42017054718). RESULTS: Nine trials including 3069 patients were analyzed. Compared with control group, SGLT2 inhibitor produced absolute reduction in glycosylated hemoglobin A1c (HbA1c) (MD -1.35%, 95% confidence interval [CI] [-2.36 to -0.34], P = .009), fasting plasma glucose (FPG) (MD -1.01 mmol/L, 95%CI [-1.98 to 0.04], P = .04), insulin dosage (MD -4.85 U/24 hours, 95%CI [-7.42 to -2.29], P = .002), and body weight (MD -2.30 kg, 95%CI [-3.09 to -1.50], P < .00001). But the risk of hypoglycemia (OR 1.18, 95%CI [0.86, 1.61], P = . 30) and urinary tract infection (UTI) (OR 1.34, 95%CI [0.79, 2.27], P = .28) were proved as no difference and genital tract infection (GTI) with SGLT2 inhibitors was higher than control group (OR 2.96, 95%CI [1.05, 8.37], P = .04), in which cases were mild and responded to the therapy. According to the subgroup analysis, SGLT2 inhibitors had a similar effect in effective factors of both T1DM and T2DM, but the risk of GTI mainly increased in T2DM versus T1DM (T1DM OR 0.27 [0.01, 7.19], P = .43 vs T2DM OR 4.28 [2.00, 9.16], P = .0002). CONCLUSION: SGLT2 inhibitors have improved the HbA1c, FPG, and body weight when combined with insulin and decreased the dose of insulin without increasing the risk of hypoglycemia. However, SGLT2 inhibitor was proved to be related to the events of GTI, despite SGLT2 inhibitors appeared to be well tolerated. We suggest that more monitoring should be done to prevent the events of GTI, and more randomized controlled trials should be planned next step.

AIMS: Available evidence is incomplete and inconsistent in the outcomes of heart failure (HF) patients with preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF). There are also limited data on the proportions and long-term prognosis among the three HF phenotypes in China. We aimed to characterize the 5 year prognosis in three HF phenotypes according to EF in a cohort of hospitalized HF patients undergoing coronary angiography in southern China. METHODS AND RESULTS: Hospitalized patients with HF were enrolled from the Cardiorenal ImprovemeNt registry (CIN; ClinicalTrials.gov NCT04407936) between January 2007 and December 2014. HF phenotypes were defined as HFpEF (EF ≥ 50%), HFmrEF (EF 41-49%), and HFrEF (EF ≤ 40%). Kaplan-Meier and Cox proportional hazards models were constructed to examine differences in 5 year outcomes in HF patients with different phenotypes. A total of 4880 HF patients [mean age: 61.8 ± 10.3, male: 3156 (64.7%)] were included: 2768 (57%) had HFpEF, 1015 (21%) had HFmrEF, and 1097 (22%) had HFrEF. Patients with HFrEF were older than those with HFpEF (62.5 ± 10.6 vs. 61.3 ± 10.1, P < 0.001) and more likely to be male (78.0% vs. 55.9%, P < 0.001). With 5 year follow-up through the end of December 2019, 1624 (27.6%) patients died. Controlling confounding variables, declined EF category was independently associated with increased 5 year mortality {HFrEF 25.2% vs. HFpEF 13.4%, adjusted hazard ratio [aHR]: 1.85 [95% confidence interval (CI): 1.45 to 2.35]; HFmrEF 18.1% vs. HFpEF 13.4%, aHR: 1.40 [95% CI: 1.08 to 1.81]; HFrEF 25.2% vs. HFmrEF 18.1%, aHR: 1.32 [95% CI: 1.02 to 1.71]}. CONCLUSIONS: In this Chinese cohort, patients with HFrEF account for less than a fourth of HF patients. One-sixth individuals with HF died in 5 years. HFrEF was associated with a nearly two-fold increased risk of 5 year mortality than HFpEF. Further studies are needed to prospectively evaluate the efficacy of improving treatment on outcomes in all three HF phenotypes.