MP49410-WEEK, BUT NOT 7-WEEK, DAPAGLIFLOZIN TREATMENT IMPROVES SEVERE RENAL IMPAIRMENT IN UNI-NEPHRECTOMIZED SDT FATTY RAT, A 10-WEEK MODEL OF ADVANCED RENAL COMPLICATIONS AND GLOMERULAR FILTRATION RATE DECLINE

Abstract

INTRODUCTION AND AIMS: Sodium glucose cotransporter 2 inhibition (SGLT2i) represents a promising new class of glucose lowering drugs but may not be recommended in type 2 diabetic patients with severe renal impairment. Here we evaluated the effects of dapagliflozin (DAPA) treatment in uni-nephrectomized Spontaneously Diabetic Torii (SDT) fatty rat. This novel hypertensive, obese, type 2 diabetic model, develops advanced renal complications and >50% glomerular filtration rate (GFR) decline within 10 weeks. METHODS: Male, 6-week old SDT fatty rats underwent unilateral nephrectomy. After a 1-week recovery, rats were put on a salt-supplemented (Purina 5008 chow diet and drinking water supplemented with 0.3% salt) for 10 weeks. Rats were treated without or with DAPA 1mg/kg/day in the chow diet either upon diet start (10-week treatment) or after 3 weeks of diet to enhance kidney complications (7-week treatment). A group of control/sham operated rats was included to evaluate kidney complications induced by nephrectomy and salt supplementation. RESULTS: After 10 weeks of diet and compared to Sham rats, albuminuria was 206% higher in Unx control rats, while plasma creatinine clearance and GFR (FITC-inulin injection) were substantially reduced by 46 and 60% (p<0.01 vs. Sham). Histology analysis (Periodic acid-schiff, ED1 immunostaining and Sirius Red) confirmed advanced glomerulosclerosis, inflammation and fibrosis in Unx control rats (all scores p<0.05 vs. Sham). Compared to Unx control rats, both 7-week and 10-week DAPA treatments of Unx rats strongly reduced hyperglycemia by up to 70%, and % HbA1c by up to 6% (both p<0.01 vs. control). The 7-week treatment with dapagliflozin did not change GFR decline, glomerulosclerosis, inflammation and fibrosis scores. In contrast, the 10-week treatment with dapagliflozin significantly reduced glomerulosclerosis, inflammation and fibrosis scores. Despite these substantial histopathological improvements, GFR remained unaltered, which could be linked to tubuloglomerular feedback under SGLT2 inhibition. CONCLUSIONS: Our data demonstrate that a 10-week, but not 7-week, treatment with dapagliflozin, significantly prevents advanced renal complications in uninephrectomized SDT fatty rats. These results suggest that long-term treatment with a SGLT2 inhibitor may be beneficial in regards with kidney complications in the context of type 2 diabetes.