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SGLT2 inhibition decreases oxygen consumption and increases oxygen tension in diabetic rats
Author(s) -
Liu Zhizhao,
Hall Elanore,
Singh Prabhleen
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.621.5
Subject(s) - empagliflozin , diabetes mellitus , medicine , endocrinology , diabetic nephropathy , renal cortex , oxygen tension , glycosuria , type 2 diabetes , renal function , streptozotocin , oxygen , kidney , chemistry , organic chemistry
Diabetes is a major cause of chronic kidney disease. Recent data reports that sodium‐glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin (EMPA), slows down the progression of diabetic nephropathy in type 2 diabetes mellitus. Here we investigate the effects of empagliflozin on kidney function, renal oxygen tension and oxygen consumption in streptozotocin‐induced diabetic rats (type 1 diabetes mellitus) to understand the underlying protective mechanism of empagliflozin on kidney disease. Method Age‐matched male Wistar rats were randomly divided into four groups: control, control+EMPA (30 mg/kg/day oral gavage), diabetes, and diabetes+EMPA. Two weeks later, GFR was estimated by clearance of 3 H‐inulin. Total renal blood flow (RBF) was measured using an ultrasound probe placed around the left renal artery. Blood gas parameters and total oxygen consumption were analyzed on samples drawn from the left renal vein and femoral artery. In another set of experiments, intrarenal oxygen tension was measured in the renal cortex and medulla by oxygen microsensor. Results Compared with controls, diabetes displayed a slight higher RBF, decreased arterial oxygen saturation (85% VS. 92%) and decreased oxygen partial pressure (65 mmHg VS. 81 mmHg). Oxygen consumption increased in diabetes compared to controls (0.31 ml/min VS. 0.16 ml/min), and oxygen tension in renal cortex (39 mmHg VS. 54 mmHg) and medulla (35 mmHg VS. 40 mmHg) were lower in diabetes. Empagliflozin prevented the diabetes induced‐alterations in oxygen consumption (0.21 ml/min), and restored the decreased oxygen tension in renal cortex (45 mmHg), not in renal medulla (35 mmHg). Empagliflozin reduced 48% of the insulin requirement with 14% lower blood glucose level in diabetic groups. Conclusion Empagliflozin prevents diabetes‐induced alteration in kidney oxygen metabolism by reducing proximal renal glucose reabsorption which reduced total renal oxygen consumption while increased renal cortex oxygen tension. Empagliflozin reduced blood glucose levels in a T1DM animal model. These improvements provide insights into the mechanisms by which empagliflozin reduces the rates of clinically relevant renal end points. Additional molecular mechanisms and mitochondrial function in response to SGLT2 inhibition in diabetes is being investigated. Support or Funding Information American Diabetes AssociationVA Merit Award