Studies have found overexpressed integrin-linked kinase (ILK) and disturbed matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) ratio in diabetic nephropathy epithelial-mesenchymal transition (EMT). However, the underlying mechanisms of EMT and the inhibiting effect of rhein need further understanding. The aim of this study was to investigate the possible regulating effects of ILK towards MMP-9/TIMP-1 ratio in EMT and the inhibiting effect of rhein. The characteristic epithelial marker and mesenchymal marker of EMT were examined by cytoimmunostaining, real-time reverse transcription polymerase chain reaction (real-time RT-PCR) and Western blot. To observe the EMT inhibiting effects of rhein, specific ILK-small interfering RNA (ILK-siRNA) was used as a positive control. The results showed that in high glucose conditions, overexpression of ILK and an abnormal changing of MMP-9/TIMP-1 ratio occurred; ILK inhibition by siRNA could adjust MMP-9/TIMP-1 ratio to near normal. Meanwhile, rhein inhibited the overexpressing ILK and inhibits high glucose-induced EMT; the effect was similar to that of ILK-siRNA. The decreased expression of ILK regulated by rhein contributed to the adjustment of the MMP-9/TIMP-1 ratio. Our data indicates that rhein inhibits high glucose-induced-EMT partially through the inhibition of ILK expression and regulates the MMP-9/TIMP-1 ratio in HK-2 cells. This mechanism may be associated with rhein's effect of ILK suppression.

Nephrotoxicity is a major side-effect of cisplatin in chemotherapy, which can occur acutely or progress into chronic kidney disease (CKD). The protein p53 plays an important role in acute kidney injury induced by cisplatin, but its involvement in CKD following cisplatin exposure is unclear. Here, we address this question by using experimental models of repeated low-dose cisplatin (RLDC) treatment. In mouse proximal tubular BUMPT cells, RLDC treatment induced p53 activation, apoptosis, and fibrotic changes, which were suppressed by pifithrin-α, a pharmacologic inhibitor of p53. In vivo, chronic kidney problems following RLDC treatment were ameliorated in proximal tubule-specific p53-knockout mice (PT-p53-KO mice). Compared with wild-type littermates, PT-p53-KO mice showed less renal damage (KIM-1 positive area: 0.97% vs. 2.5%), less tubular degeneration (LTL positive area: 15.97% vs. 10.54%), and increased proliferation (Ki67 positive area: 2.42% vs. 0.45%), resulting in better renal function after RLDC treatment. Together, these results indicate that p53 in proximal tubular cells contributes significantly to the development of chronic kidney problems following cisplatin chemotherapy.

BackgroundHigh- and low-flux hemodialysis (HFHD and LFHD, respectively) are dialysis procedures designed to eliminate blood toxins that accumulate in end-stage renal disease. HFHD may reduce vascular calcification by removing serum fibroblast growth factor 23 (FGF-23). However, whether HFHD is better than LFHD is still under debate. We therefore compared the efficacy of HFHD and LFHD in controlling FGF-23 and vascular calcification.Material/MethodsFifty hemodialysis patients were recruited and randomly treated with either HFHD or LFHD. Fasting venous blood was collected at baseline, six months, and twelve months after the treatment. We then measured levels of FGF-23, calcium, phosphorus, parathyroid hormone, and alkaline phosphatase. Further, abdominal lateral radiographs were taken to calculate aorta abdominalis calcification scores (AACs).ResultsCompared to the LFHD group, FGF-23 and AACs in the HFHD group significantly decreased after 12 months treatment (p=0.049 and p=0.002, respectively). AACs were positively correlated with FGF-23 in all patients (p=0.004), the HFHD group alone (p=0.040), and the LFHD group alone (p=0.037). We also found that older patients, patients with higher blood phosphorus levels, and higher FGF-23 levels had an increased risk of aorta abdominalis calcification (p=0.048, p=0.003, p=0.001, respectively). HFHD was more able to reduce the risk of aorta abdominalis calcification than LFHD (p=0.003).ConclusionsFGF-23 is an independent risk factor for the development of vascular calcification. HFHD may benefit hemodialysis patients by reducing serum FGF-23 levels and controlling vascular calcification.