| Objective: To investigate the renal protective effect and other adverse effects of different doses of sodium glucose cotransporter 2 inhibitor（SGLT2i）canagliflozin（CGLZ）on nephrotic syndrome model rats induced by adriamycin（ADR）.Methods: 56 SD rats were haphazardly separate into NG（normal group,n = 8）and modeling group（n = 48）.The model group was injected with ADR 4 mg/kg through caudal vein,and ADR 2.5 mg/kg was injected again after an interval of 1 week.After successful modeling,they were arbitrarily splited into 6 groups: MG（modeling group）,PG（PAT group）,SSCG（small-dose CGLZ group）,LSCG（large-dose CGLZ group）,SUCG（smal-dose CGLZ + PAT group）and LUCG（large-dose CGLZ +PAT group）,each group contained eight rats.Drugs were given by intragastric administration at 8 a.m,every day for 6 weeks.Urine was taken for24-hour urine total protein（24h-UTP）quantitative detection 1 day before gavage and at the end of 2,4 and 6 weeks after gavage.Urine phosphorus and urine calcium were detected at the end of the 6th week,the rats were narcotized by intraperitoneal injection of Chloral Hydrate and ultrasound and bone mineral density were detected.The next morning,after the same method of anesthesia,5ml of abdominal aorta blood was extracted by laparotomy.Albumin（ALB）,Triglyceride（TG）,Cholesterol（TC）,Low density lipoprotein（LDL）,Urea nitrogen（Urea）,Creatinine（Crea）,Alkaline phosphatase（ALP）,Serum calcium and Serum phosphorus were sent for examination.After blood sampling,the right kidney was fixed in10% formalin for more than 48 hours for pathological examination.Pearson or Spearman correlation analysis was performed on the experimental data.Results:（1）The changes of general situation and kidney index（KI）.（1）The activity of the model rats was reduced,the weight was decreased,the hair without luster,and there were loose stools from time to time.After the treatment of different drugs,the general situation of rats in each drug groups were significantly improved,and the changes of body weight were firstly decreased and then gradually increased.（2）Contrast with NG group,KI was step-up in each group,contrast with MG and PG groups,KI was increased in SSCG and LUCG groups.（2）Renal histopathological changes.The glomerular morphology and structure of NG group was normal,and the capillary lumen was not narrowed,the epithelial cells of kidney tubules were trimly tactic.In MG group,Part of the glomerulus were sclerotic and atrophic,inflammatory cells infiltrated,the epithelial cells of the renal tubules swelled,capillary lumen dilated,more protein casts were found in the lumen,and interstitial fibrosis was obvious.All of the drug treatment groups showed different degrees of changes,including glomerular morphology was restored,protein casts were lessened,epithelial cell swelling and interstitial fibrosis were reduced,but the cell proliferation and inflammatory cell infiltration in LUCG group were more obvious than those in other drug treatment groups.（3）The changes of24h-UTP.Compared to NG group,24h-UTP in model group increased significantly 1d before gavage and throughout the treatment period,the model was successfully established.Compared with MG group,24h-UTP in SSCG group decreased after 2 weeks of gavage treatment,and continued to take effect.After the 6th week of treatment,24h-UTP decreased in all drug treatment groups.The efficacy of CGLZ alone or low-dose CGLZ+PAT was better than PAT alone and high-dose CGLZ+PAT.（4）Changes of the blood biochemical criterion in nephrotic syndrome.In Comparison with NG group,ALB in MG group decreased,Urea,TG,TC and LDL in MG group increased;ALB decreased and TG and LDL increased in PG group,Urea increased in LUCG group.Compared with MG group,ALB in all groups contained CGLZ increased,TG decreased in SSCG group,TC and LDL decreased in SUCG group.It suggests that CGLZ can increase serum ALB and decrease blood lipid.（5）Changes of bone metabolism and its related indexes.（1）Blood phosphorus: compared with NG group,blood phosphorus in PG and LSCG groups was increased;Compared with MG group,blood phosphorus in PG group was increased.The results showed that PAT and high dose of CGLZ could increase blood phosphorus.（2）Blood ALP: Compared with NG group,ALP was increased in MG,PG,LSCG and LUCG groups,indicating that molding,PAT,high dose of CGLZ or the combination of the above two drugs can lead to increased ALP,which may be related to osteoporosis.（3）Urinary calcium: compared with NG group,the urinary calcium in LSCG,SUCG and LUCG groups was increased;Compared with MG group,urinary calcium in SUCG and LUCG groups was increased.These results suggest that high dose of CGLZ or CGLZ combined with PAT can lead to increased urinary calcium excretion.（4）Systemic bone mineral content（BMC）: Compared with NG group,whole body BMC in PG and LUCG groups was decreased;Compared with MG group,the BMC of PG group was decreased.These results suggest that PAT or PAT combined with high dose of CGLZ can decrease BMC in the whole body,which is speculated to be related to osteoporosis.（5）Regional bone mineral density（BMD）: Compared with NG group,BMD of trunk and ribs in PG and LUCG groups were decreased,and pelvic BMD in all drug treatment groups were decreased;Compared with MG group,rib BMD in PG and LUCG groups was decreased.The results showed that both PAT and CGLZ could cause the decline of pelvic BMD,while PAT or PAT combined with high dose CGLZ could lead to the decline of trunk and rib BMD,increasing the risk of osteoporosis and fracture.（6）The changes of color doppler flow imaging and related indicators.（1）Cortical thickness of right kidney: compared with NG group,the cortical thickness of right kidney in each group decreased,and compared to MG and PG groups,the cortical thickness of right kidney in each group treated with CGLZ increased.It suggests that CGLZ can prevent the thinning of renal cortex.（2）In Comparison with NG group,PI,RI and S/D of renal artery in MG group were elevated;Contrast with MG group,PI in SSCG group was katabatic,RI in PG group was decreased,S/D in all drug groups except LUCG group was decreased.PI,RI and S/D in LUCG group were higher than those in the other medication groups.These results indicate that low dose of CGLZ or PAT can reduce renal blood flow resistance,while high dose of CGLZ+PAT can increase renal blood flow resistance.（7）The changes of contrast-enhanced ultrasound and related indexes.Compared to NG group,TTP,AT and AUC in MG group were rising,while DPI and A were decreased.A decreased and AUC increased in LUCG group.In Comparison with MG,TTP,AT and AUC in all drug treatment groups decreased.Except SSCG group,DPI in other drug groups increased.Compared to other medication groups,AUC in LUCG group increased.These results indicated that except the high-dose CGLZ+PAT group,the other drug treatment groups improved renal blood perfusion to varying degrees.（8）The correlation analysis.24h-UTP was negatively correlated with serum ALB.Renal blood flow index RI was positively correlated with PI,S/D and serum Urea.CEUS parameters AUC and DPI were positively correlated with renal cortical thickness and 24h-UTP,respectively.Conclusions:（1）CGLZ can reduce urinary protein,regulate blood lipid,reduce renal blood flow resistance,improve renal blood perfusion and reduce pathological damage,So that the kidneys are protected.Therefore,CGLZ can be used in NS alone or in conjunction with PAT to increase the therapeutic effect.（2）High dose CGLZ combined with PAT lead to increased renal blood flow resistance,increased serum Urea and ALP,abnormal metabolism of calcium and phosphorus,and decreased BMD and BMC.（3）In the process of clinical medication,it is suggested to carefully consider the dose of CGLZ and dynamically monitor blood and urine biochemistry,renal blood flow resistance and perfusion,bone metabolism and other related indicators.Achieve individualized and rational drug use. |
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