| Objective:Worldwide,the incidence of kidney stones is rising year by year,and the reason for this trend is not clear.In recent years,research on the cause of urinary stones and drug prevention are more and more concerning by the majority of clinicians and research workers.The Second Hospital of Tianjin Medical University urolithiasis treatment center is the largest prevention and treatment of urolithiasis base in North China,in order to assess the distribution of different components of urinary calculi in North China,but also for the future for urinary depth pathogenesis of stones lay the foundation for research and drug treatment,we retrospectively analyzed clinical data in our center.On this basis,we focused on the most common stone composition of that calcium oxalate stone prevention and drug treatment carried out further research,we chose inexpensive,easy to popularize,but also has many potential clinical applications of the drug metformin as our study,having a system assess whether inhibition of calcium oxalate stone formation,as well as specific mechanisms play this role.Methods:1.We sought to determine the trends in pathogenesis of urolithiasis based on urinary stone analyses.A total of 2813 eligible urinary stone samples from different patients between 2002 and 2014 in our center were collected.Infrared spectroscopy was used for urinary calculi analysis.Logistic regression analysis was used to investigate the relationship of urinary calculi composition and calendar month(season),gender and age in north China during the past 13 years.2.MTT assays were carried out to determine the protection of metformin from oxalate-induced cytotoxicity.The intracellular superoxide dismutase(SOD)activities and malondialdehyde(MDA)levels were measured in vitro.Male Sprague-Dawley rats were divided into control group,ethylene glycol(EG)treated group and EG + metformin treated group.Oxidative stress and crystal formations were evaluated in renal tissues after 8-week treatment.3.Cytotoxicity of MDCK and HK-2 cells was carried out by Cell Counting Kit-8 assay in vitro.Subsequently,the mRNA transcriptions and protein expression of MCP-1 and OPN were detected by quantitative RT-PCR,western blot and ELISA.Male Sprague-Dawley rats were divided into control group,ethylene glycol(EG)group and EG + metformin group.The expression of MCP-1 and OPN,as well as crystal formations were evaluated in renal tissues after 8-week treatment.Results:1.Calcium containing calculi were the most frequent with an overall incidence of 84.1%.calcium phosphate(CaP)or magnesium ammonium phosphate(MAP)stones were more frequent in females,while monohydrate calcium oxalate(COM),dihydrate calcium oxalate(COD)or uric acid(UA)stones were more common in males.Older individuals were associated with an increased risk of UA stones and a decreased risk of COD,CaP or Cystine stones.Additionally,from 2002 to 2014,the frequency of COD and MAP stone increased,whereas the trend of CaP,UA and Cystine stones decreased.However,calendar month(season)was not significantly associated with differences in composition.2.Metformin significantly inhibited the decrease of the viability in MDCK cells and HK-2 cells induced by oxalate.Besides,metformin markedly prevented the increased concentration of MDA and the decreased tendency of SOD in oxalate-induced MDCK cells and HK-2 cells.In vivo,the increased MDA levels and the reduction of SOD activity were detected in EG treated group compared with controls,while these parameters reversed in EG + metformin treated group.Kidney crystal formation in EG + metformin treated group was decreased significantly compared with EG treated group.3.The expression of MCP-1 and OPN,as well as crystal formations were evaluated in renal tissues after 8-week treatment.Metformin significantly inhibited the production of MCP-1 and OPN in vitro induced by oxalate in both mRNA and protein levels.In vivo,the increased expression of MCP-1 and OPN was detected in EG group compared with controls,while the upregulation was reversed in EG + metformin group.More importantly,renal crystal deposition in EG + metformin group was markedly decreased compared with EG group.Conclusions:1.This study provides a picture of the present distribution of urolithiasis compositions in China.From 2002 to 2014,age and gender were significantly associated with stone composition,whereas calendar month not.2.It can be concluded from our present investigation that metformin has potent antioxidant effects and could effectively reduce renal tubular injury resulting from lipid peroxidation production induced by oxalate.Additionally,to the best of our knowledge,this report is the first to show that metformin inhibits renal crystal deposition in the rat.3.The current study shows that metformin treatment protects the kidney from EG-induced CaOx crystal deposition in experimental animals,and that this protection is based,at least in part,on the correction of oxalate-induced inflammatory alterations in renal tubular epithelium cells.Additionally,to the best of our knowledge,our findings show for the first time that metformin inhibits renal crystal deposition in the rat probably by mediating the expression of OPN and MCP-1 in renal tubular cells.These intriguing findings establish metformin as a new prospective therapeutic agent for treatment of CaOx nephrolithiasis and might benefit individuals with primary hyperoxaluria or recurrent CaOx stone formation. |
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