Mutation of Klotho rs3752472 protect the kidney from the renal epithelial cell injury caused by CaOx crystals through the Wnt/ß-catenin signaling pathway.

Calcium oxalate (CaOx) is a major contributor to urolithiasis, one of the most common urological diseases. Our previous study has shown that Klotho rs3752472 polymorphism correlates with an increased risk of CaOx-related urolithiasis in human cohorts. This study aims to identify the effect of Klotho rs3752472 polymorphism on the renal epithelium injury caused by CaOx. A rat urolithiasis model was established and validated. Renal function was assessed, and histological examination was performed. The distribution and expression of Klotho in the rat model were detected by immunohistochemical staining and western blotting analysis. A renal epithelial cell line (HK2) was used and intervened by COM crystals with several concentrations and time points. Expression of Klotho and key mediators in Wnt/ß-catenin pathway were assessed by Western blotting analysis. Wide-type and mutated plasmids of Klotho rs3752472 were added in the cell culture, and the activation of Wnt/ß-catenin signaling was tested. Finally, Wide-type and mutated plasmids of Klotho rs3752472 were adoptively transferred to the rat model, and the expression of Klotho was verified. In the rat model, Klotho was mainly distributed in the renal tubular area, which significantly declined in the urolithiasis group. In vitro, COM crystals significantly inhibited the expression of Klotho and induced remarkable renal epithelial cell injury. The mutation of Klotho rs3752472 can notably enhance the expression of Klotho, as well as the protection from renal epithelial cell injury and the inhibition of Wnt/ß-catenin signaling pathway. After adoptively transferred to the rat urolithiasis model, similar results were observed for the mutation of Klotho rs3752472. Klotho was significantly correlated with the renal epithelial cell injury induced by CaOx crystals. Furthermore, the mutation of Klotho rs3752472 can remarkably enhance the expression of Klotho in renal tissues and cells, and subsequently protect the renal epithelial cell from the formation of CaOx crystals through the inhibition of Wnt/ß-catenin signaling pathway.

pH-triggered charge-reversal and redox-sensitive drug-release polymer micelles codeliver doxorubicin and triptolide for prostate tumor therapy.

AIM: To significantly promote cancer cell uptake and to achieve combination therapy and on-demand drug release, a pH-triggered charge-switchable and redox-responsive drug-release nanovehicle was developed in this study. MATERIALS AND METHODS: The nanocarrier was constructed by conjugating 3,3'-dithiodipropionic acid-modified doxorubicin (DTPA-DOX) and 2,3-dimethylmaleic anhydride (DMA) to the side amino groups of poly(ethylene glycol)-b-poly(L-lysine) (PEG-b-PLL) and by encapsulating triptolide (TRI) into the hydrophobic core. The surface charge of the obtained nanocarriers (DA-ss-DT) can change from negative to positive in response to tumor extracellular acidity pH, and the nanocarriers capably release two drugs in response to intracellular high glutathione (GSH) environment. RESULTS: Compared to the control group, the in vitro cellular uptake of DA-ss-DT by human prostate cancer PC-3 cells was significantly promoted in slightly acidic conditions, and the drug could be rapidly released in the high concentration of GSH conditions. The in vitro and in vivo antitumor experiments exhibited that the DA-ss-DT nanoparticles have a great antitumor effect in comparison to the control group. CONCLUSION: These findings demonstrated that the DA-ss-DT nanoparticles supply a useful strategy for promoting cellular uptake and synergetic anticancer therapy.

Renal endometriosis tends to be misdiagnosed as renal tumor: a rare case report.

Renal endometriosis is a rare disease for which the mechanisms of pathogenesis are still unclear. As such, early diagnosis and an appropriate treatment are often delayed because of the tendency to be misdiagnosed as a renal tumor. In October 2013 we performed a radical nephrectomy for a 37-year-old woman with renal endometriosis who was preoperatively misdiagnosed as having a right renal tumor. Avoiding the misdiagnosis of renal endometriosis requires a detailed case history, especially regarding whether the cyclicity of lumbodorsal pain and hematuria correlates with patients' menstrual cycles. Imaging examinations are commonly helpful for localization, whereas relieving symptoms with drugs to create a hypoestrogenic state is useful for clinical diagnosis. However, a final diagnosis for renal endometriosis still must depend on histopathologic examination.

Flexible ureteroscopy with holmium laser lithotripsy: a new choice for intrarenal stone patients.

OBJECTIVE: To evaluate the efficiency and safety of flexible ureteroscopy (FURS) and holmium lithotripsy for intrarenal stones and to stratify the efficiency and safety by stone burdens of ≤20, 20-40, and ≥40 mm. METHODS: Five hundred eighty-two patients with intrarenal stones were treated with FURS and holmium lithotripsy at a single department from August 2008 to October 2013. Stone size was evaluated by calculating the cumulative stone diameter of all intrarenal stones, and stone-free status was defined as the absence of any stone or stone fragment <1 mm in the kidney. RESULTS: Data analysis revealed a mean stone burden of 21.8 ± 7.6 mm. The overall primary stone-free rate (SFR) was 65.3%, which increased to 89.0% 6 months after the first surgery. Complications developed in 6.7% of patients. A significant difference was found between lower-calyx stones and other stones (p < 0.001; p = 0.006), while noncalcium stones had a much higher SFR than calcium stones (p < 0.001; p = 0.04). CONCLUSION: Our study showed that the overall renal SFR with the use of FURS and holmium lithotripsy was satisfactory, with a relatively low complication rate. We believe that FURS with holmium lithotripsy could be a valuable choice for patients with renal stones, especially for patients with a cumulative stone burden ≤40 mm.

Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China.

BACKGROUND/AIMS: The incidence of urolithiasis has considerably increased throughout the world in the last two decades. Clinical researches have showed an association between oxidative stress and stone formation. Emerging evidence indicated a novel function for klotho protein in anti-oxidative stress. In this study, we aimed at investigating a possible relationship between klotho gene polymorphisms and the risk of calcium oxalate urolithiasis in the population of Han nationality in Eastern China. METHODS: Klotho gene polymorphisms rs3752472 in exon3, rs650439 in intron 4 and rs577912 in intron 1 were investigated in 426 patients with calcium oxalate stones compared with 282 age-matched healthy volunteers with no history of stone formation, using TaqMan SNP Genotyping Assays. RESULTS: Significant differences were found between rs3752472 and the risk of nephrolithiasis as CC genotype of rs3752472 klotho polymorphism had almost 2-fold increased stone risk compared with the heterozygote genotype CT and homozygous genotype TT(95% CI=1.013-2.255, OR=1.512,p=0.043). CONCLUSION: Our results showed that the rs3752472 polymorphism of klotho gene is associated with the risk of calcium oxalate urolithiasis and may act as a risk factor during stone formation in our study population.