Key result
Dapagliflozin significantly decreased urine angiotensin II levels (3.2 vs 108.1 pg/ml) and attenuated oxidative stress and interstitial fibrosis compared to saline in a rat model of type 2 diabetes.
Why the study?
Does dapagliflozin improve diabetic nephropathy by suppressing the renal renin-angiotensin system in an animal model of type 2 diabetes?
Does dapagliflozin improve diabetic nephropathy by suppressing the renal renin-angiotensin system in an animal model of type 2 diabetes?
Dapagliflozin ameliorates diabetic nephropathy in a type 2 diabetes rat model by suppressing renal renin-angiotensin system activation, oxidative stress, and interstitial fibrosis.
This is the authors' abstract. We don't add key points for this paper.
BACKGROUND: Renal renin-angiotensin system (RAS) activation is one of the important pathogenic mechanisms in the development of diabetic nephropathy in type 2 diabetes. The aim of this study was to investigate the effects of a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, dapagliflozin, on renal RAS in an animal model with type 2 diabetes. METHODS: Dapagliflozin (1.0 mg/kg, OL-DA) or voglibose (0.6 mg/kg, OL-VO, diabetic control) (n = 10 each) was administered to Otsuka Long-Evans Tokushima Fatty (OLETF) rats for 12 weeks. We used voglibose, an alpha-glucosidase inhibitor, as a comparable counterpart to SGLT2 inhibitor because of its postprandial glucose-lowering effect without proven renoprotective effects. Control Long-Evans Tokushima Otsuka (LT) and OLETF (OL-C) rats received saline (n = 10, each). Changes in blood glucose, urine albumin, creatinine clearance, and oxidative stress were measured. Inflammatory cell infiltration, mesangial widening, and interstitial fibrosis in the kidney were evaluated by histological analysis. The effects of dapagliflozin on renal expression of the RAS components were evaluated by quantitative RT-PCR in renal tissue. RESULTS: After treatment, hyperglycemia and urine microalbumin levels were attenuated in both OL-DA and OL-VO rather than in the OL-C group (P < 0.05). The urine angiotensin II (Ang II) and angiotensinogen levels were significantly decreased following treatment with dapagliflozin or voglibose, but suppression of urine Ang II level was more prominent in the OL-DA than the OL-VO group (P < 0.05). The expressions of angiotensin type 1 receptor and tissue oxidative stress markers were markedly increased in OL-C rats, which were reversed by dapagliflozin or voglibose (P < 0.05, both). Inflammatory cell infiltration, mesangial widening, interstitial fibrosis, and total collagen content were significantly increased in OL-C rats, which were attenuated in OL-DA group (P < 0.05). CONCLUSION: Dapagliflozin treatment showed beneficial effects on diabetic nephropathy, which might be via suppression of renal RAS component expression, oxidative stress and interstitial fibrosis in OLETF rats. We suggest that, in addition to control of hyperglycemia, partial suppression of renal RAS with an SGLT2 inhibitor would be a promising strategy for the prevention of treatment of diabetic nephropathy.
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May inform SGLT2i mechanisms in diabetic kidney disease; leaves open human translation from this rat model.
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Shin et al. (2016) studied Type 2 diabetes and diabetic nephropathy (animal model) (n=40). Dapagliflozin vs. Saline (diabetic control) and Voglibose (0.6 mg/kg) was evaluated on Urine Angiotensin II level (pg/ml) (p=<0.05). Dapagliflozin significantly decreased urine angiotensin II levels (3.2 vs 108.1 pg/ml) and attenuated oxidative stress and interstitial fibrosis compared to saline in a rat model of type 2 diabetes.
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