The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

Assessing the influence of acute kidney injury on the mortality in patients with acute myocardial infarction: a clinical trail.

OBJECTIVES: Acute kidney injury (AKI) increases the risk of death following acute myocardial infarction (AMI). In this current study, we tried to understand the role of newly KDIGO defined AKI in AMI-induced early and late mortality. METHODS: We retrospectively analyzed the clinical data of AMI patients (totaling 1371 cases) from the hospital's computer database. And AKI was defined based on the KDIGO criteria but GFR or urinary output assessment was not used. Subsequently, we compared the association of AKI with 30-day and 30-day to 5-year all-cause mortality, using multivariate COX regression analysis with two models. RESULTS: We observed the development of AKI in 410 (29.9%) patients during the hospital stay. The 30-day and 30-day to 5-year mortality rates were 5.6% and 11.3%, respectively, in 1371 AMI patients. Further, adjusted Cox regression analysis based on model 1 revealed that AKI severity was an independent risk factor of 30-day mortality, while AKI Stage 3 was an independent predictor of 30-day to 5-year mortality. Adjusted Cox regression analysis based on model 2 revealed that normal baseline renal function with AKI and impaired renal function with AKI were independent risk factors of 30-day mortality, while normal baseline renal function with AKI and impaired renal function with AKI were identified to be independent predictors of 30-day to 5-year mortality. CONCLUSIONS: Whether the baseline renal function decreased or not, AKI strongly correlated with short- and long-term all-cause mortality in patients with AMI. Specifically, the short-term mortality of AMI patients increased with more severe AKI.

Risk factors of acute kidney injury after acute myocardial infarction.

OBJECTIVES: To study the risk factors for acute kidney injury (AKI) in-patients with acute myocardial infarction (AMI). METHODS: A total of 1371 cases of adult in-patients with AMI in the First People's Hospital of Changzhou from January 2008 to December 2012 were retrospectively analyzed. Based on the occurrence of AKI diagnosed according to the 2012 KDIGO AKI criteria, they were divided into AKI group and non-AKI group and further into conservative treatment groups, coronary angiography (CAG) groups, and coronary artery bypass grafting (CABG) groups based on the timing of AKI occurrence, respectively. Related risk factors of AKI were analyzed by univariate and multivariate logistic regressions. RESULTS: 410 (29.9%) developed AKI. Patients with AKI had significantly increased in-hospital mortality than patients without AKI. Multivariate logistic regression analysis showed that decreased baseline eGFR, increased fasting plasma glucose (FPG), use of diuretics and Killip grade IV were independent risk factors of AKI, while increased DBP on admission was a protective factor for patients in conservative treatment group. Decreased baseline eGFR, increased FPG, use of diuretics, intraoperative hypotension and acute infection were independent risk factors of AKI for patients in the CAG group. Decreased baseline eGFR, increased FPG, use of diuretics and low cardiac output syndrome after operation were independent risk factors of AKI for patients in the CABG group. CONCLUSIONS: AKI is a common complication and associated with increased mortality after AMI. Decreased baseline renal function, increased FPG and use of diuretics were common independent risk factors of AKI after AMI.