Abstract Body: Introduction: Diabetes is a leading cause of chronic kidney disease (CKD) and progression to end-stage renal disease. Previous studies showed elevated urinary angiotensin-converting enzyme 2 (ACE2) and neprilysin (NEP) in diabetic db/db mice, which was attenuated by normalizing hyperglycemia and glycosuria with the PPAR- γ agonist, rosiglitazone and physical exercise training. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as canagliflozin, lower hyperglycemia by inhibiting renal glucose reabsorption and induce glycosuria.
Aim: The study compared the effects of canagliflozin and the PPAR-γ agonist pioglitazone on urinary and renal ACE2, and a disintegrin and metalloprotease 17 (ADAM17), along with albuminuria and renal injury markers such as neutrophil gelatinase-associated lipocalin (NGAL), arginase-II, and sirtuin-1 (SIRT1).
Materials & Methods: Six-week-old db/db (n=20) and lean control mice (n=20) were treated with regular chow or chow supplemented with canagliflozin or pioglitazone (20 mg/kg/day) for 10-15 weeks. Metabolic and renal parameters were measured weekly and urine was collected for evaluating glycosuria, protein expression and enzyme activity.
Results: Diabetic db/db mice exhibited augmented hyperglycemia compared to lean controls (400 ± 45.2 mg/dL vs 100 ± 6.85 mg/dL), increased renal ADAM17, Arginase II and decreased SIRT1. In addition, db/db mice showed significant increased urinary ACE2, and NGAL levels (p<0.001). Both treatments significantly reduced blood glucose in db/db mice. Canagliflozin induced glycosuria in diabetic and lean control mice and paradoxically increased urinary ACE2 and albuminuria. However, pioglitazone decreased renal ADAM17 and attenuated urinary ACE2 and albuminuria. Both treatments increased renal SIRT1, decreased arginase-II and attenuated urinary NGAL. Data are presented as mean ± SEM for each group (n =5–8).
Conclusion: Canagliflozin-induced glycosuria may contribute to increased albuminuria and urinary ACE2 shedding, possibly linked to elevated ADAM17 activity. Conversely, pioglitazone demonstrated a more favorable renal profile, with reduced albuminuria and ACE2 shedding. Both treatments conferred renoprotective effects, potentially driven by upregulation of renal SIRT1 and downregulation of NGAL and arginase-II.