One of the most prevalent male urogenital anomalies is hypospadias. The general etiology of hypospadias is still not completely clear, despite the fact that the number of patients with the hypospadias is rising. HNF-1α was predicted as the most activated upstream regulator of severe hypospadias in our previous research. Our study aims to investigate the mechanism by which HNF-1α regulates hypospadias. We found that HNF-1α was highly expressed in hypospadias tissues, and was positively associated with fibrinogen related genes FGA and FGB, respectively. In animal experiments, silencing of HNF-1α resulted in a more narrow urethral groove, and a decreased periurethral pathologic fibrosis. Meanwhile, the inflammation cytokines and oxidative stress related factors were significantly reduced after inhibition of HNF-1α expression. In addition, the protein levels of STAT3, FGA and FGB were also depressed after HNF-1α knockdown. Mechanistically, we showed that the HNF-1α transcriptionally activated STAT3, and subsequently increased the expressions of FGA and FGB. Additionally, suppression of HNF-1α improved the murine hypospadias via inactivating the STAT3. Therefore, our findings confirmed that HNF-1α promoted hypospadias and periurethral fibrosis by activating STAT3. Targeting HNF-1α might the future direction for hypospadias treatment.
Drug-induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor-1α (HNF-1α) and glutathione S-transferase A1 (GSTA1) are important in regulating liver-specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2-ceramide is a pro-apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF-1α and GSTA1 in a cellular model of DILI and whether oltipraz and C2-ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP-induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c-Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF-1α and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 μmol/L) was similar to a JNK inhibitor and significantly increased HNF-1α/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2-ceramide (8 μmol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c-Jun, and markedly decreased HNF-1α/GSTA1 expression, C2-ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF-1α/GSTA1 are involved in the process of DILI. Inhibiting JNK up-regulated HNF-1α and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2-ceramide might affect the expression of HNF-1α/GSTA1 though JNK signaling.
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