Abstract 4365541: Dagliflozin Ameliorates Perirenal Adipose Tissue-Derived Leptin-Induced Renal Tubular Injury In Obese Hypertensive Mice

Background: Adipocytokines leptin from perirenal adipose tissue (PRAT) is implicated in the pathogenesis of obesity-associated hypertension. This study was to demonstrate whether dagliflozin ameliorates renal tubular damage in obese hypertensive mice by reducing leptin from perirenal adipose tissue. Methods: Eight-week-old male C57BL/6 mice were used to establish an obese model by feeding of a high-fat diet for twenty weeks, and then dagliflozin (10mg/kg/d) was intervened for eight consecutive weeks. Human proximal tubular cell line (HK-2) were co-cultured with PRAT conditioned medium (PRAT-CM) with or without dagliflozin and inhibitors. Results: Obese mice exhibited with perirenal adipose tissue accumulation, hypertension, reduced urinary sodium excretion, elevated urinary albumin-to-creatinine ratio. Dagliflozin treatment significantly decreased PRAT-derived leptin secretion and blood pressure, restored impaired urinary sodium excretion, alleviated renal oxidative stress and interstitial fibrosis. Leptin concentration was significantly lower in PRAT-CM from dagliflozin-treated mice than that of obese group. In vitro, dagliflozin inhibited the leptin production and secretion in insulin-resistant 3T3-L1 adipocytes by regulating the PI3K/AKT and ERK1/2 signaling pathways. NADPH oxidase 4 (NOX4) expressions and ROS levels were increased and adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation was decreased in HK-2 cells when co-cultured with PRAT-CM of obese group, accompanied by elevated Na+-K+-ATPase activity, dagliflozin could counteract the pro-sodium uptake effect of PRAT-derived leptin by activating AMPK to inhibit NOX4/ROS/Na+-K+-ATPase oxidative stress amplification loop, and alleviate cell injury in renal tubules. Conclusions: Dagliflozin reduces leptin expression in perirenal adipose tissue and decreases Na+-K+-ATPase activity to increase urinary sodium excretion, lower blood pressure, and ameliorate renal tubular injury.