Ruan, Mengna

AbstractCisplatin nephrotoxicity has been considered as serious side effect caused by cisplatin‐based chemotherapy. Recent evidence indicates that renal tubular cell apoptosis and inflammation contribute to the progression of cisplatin‐induced acute kidney injury (AKI). Hepatocyte nuclear factor 1β (HNF1β) has been reported to regulate the development of kidney cystogenesis, diabetic nephrotoxicity, etc However, the regulatory mechanism of HNF1β in cisplatin nephrotoxicity is largely unknown. In the present study, we examined the effects of HNF1β deficiency on the development of cisplatin‐induced AKI in vitro and in vivo. HNF1β down‐regulation exacerbated cisplatin‐induced RPTC apoptosis by indirectly inducing NF‐κB p65 phosphorylation and nuclear translocation. HNF1β knockdown C57BL/6 mice were constructed by injecting intravenously with HNF1β‐interfering shRNA and PEI. The HNF1β scramble and knockdown mice were treated with 30 mg/kg cisplatin for 3 days to induce acute kidney injury. Cisplatin treatment caused increased caspase 3 cleavage and p65 phosphorylation, elevated serum urea nitrogen and creatinine, and obvious histological damage of kidney such as fractured tubules in control mice, which were enhanced in HNF1β knockdown mice. These results suggest that HNF1β may ameliorate cisplatin nephrotoxicity in vitro and in vivo, probably through regulating NF‐κB signalling pathway.

Clearance of protein-bound uremic toxins (PBUTs) by dialysis is a challenge in the treatment of uremic patients. Shen-Shuai-Ning (SSN), a traditional Chinese medicine formulation, has been used commonly in China to retard kidney disease progression and decrease uremic toxins in chronic kidney disease (CKD) patients, but the effects of SSN on serum PBUTs in dialysis patients were not investigated. We conducted a randomized controlled trial in patients on peritoneal dialysis (PD) at dialysis center of Changzheng Hospital to evaluate the effects of SSN on serum PBUTs. Participants with SSN intervention took 5 g SSN granule three times daily for 12 weeks, while the baseline medications and dialysis prescriptions remained during the study in all patients. The serum concentrations of indoxyl sulphate (IS) and p-cresol sulphate (PCS) were determined by HPLC/MS/MS and biochemical parameters were assessed during the study. Sixty PD patients were enrolled and randomly allocated into SSN group and control group. Total IS level was significantly lower in SSN group than in control group at week 4, 8, and 12 (27.28 ± 18.19, 29.73 ± 19.10, and 29.41 ± 17.61 mg/l compared with 39.25 ± 20.23, 44.86 ± 23.91, and 45.34 ± 33.52 mg/l, respectively). However, there were no statistical difference of total PCS, free forms of IS and PCS concentrations between SSN group and control group during 12 weeks follow-up. Administration of SSN granule orally decreased serum total IS level effectively in uremic patients on PD with good tolerance. Benefits of PD patients’ outcomes from IS reduction by SSN awaits further large size and long duration clinical trials to verify.