Renoprotective Effects of Canagliflozin in Db/db Diabetic Mice

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Diabetes is one of the major causes of chronic kidney disease which could lead to end-stage renal disease. Previously, we have shown increased urinary angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) in db/db mouse model of type 2 diabetes, which was attenuated by normalizing hyperglycemia and glycosuria with the PPAR-γ agonist, rosiglitazone and pioglitazone. Sodium glucose co-transporter 2 (SGLT-2) inhibitor controls hyperglycemia by inhibiting renal glucose reabsorption and cause glycosuria. The aim of this study is to investigate the effect of SGLT-2 inhibitor, Canagliflozin on the urinary ACE2 and NEP and also to determine its effects on albuminuria and some of the renal injury biomarkers, neutrophil-gelatinase associated lipocalin (NGAL), sirtuins-1 (SIRT1) and arginase-II (Arg-II). Six- weeks old db/db and lean control mice were fed either normal chow or canagliflozin diet (20mg/kg/day) for 15 weeks. Metabolic and renal parameters were measured weekly and urine was collected for evaluating glycosuria, protein expression and enzyme activity. At 5 weeks, db/db mice showed significant increase in urinary ACE2, NEP and NGAL expression compared to lean mice (p<0.001). Treatment with canagliflozin for 15 weeks significantly decreased blood glucose in db/db compared to untreated mice (206.58 ± 38.35 vs. 461.82 ± 40.63 mg/dL, p<0.0001), with no effect in lean mice. Unlike PPAR-γ agonist, management of hyperglycemia with canagliflozin was not associated with attenuation of urinary albumin and ACE2. However, it attenuated urinary NGAL expression. As expected canagliflozin increased renal glycosuria in db/db and lean mice (p<0.0001) which was associated with significant increase in urinary NEP expression and activity. Western blot showed significant downregulation of SIRT1 in the kidney of 21 weeks old db/db mice which was upregulated by canagliflozin treatment. Further, there was upregulation of renal Arg-II in the db/db mice which was downregulated by canagliflozin. In conclusion, the renoprotective effects of canagliflozin could be mediated by upregulation of renal SIRT1 expression and downregulation of the renal injury markers, NGAL and Arg-II.



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