Abstract
Sodium glucose cotransporter-2 (SGLT2) inhibitors inhibit the development of diabetic nephropathy (DN). We determined whether changes in perirenal fat (PRAT) by a SGLT2 inhibitor ipragliflozin (Ipra) contribute to the suppression of DN development. High-fat diet (HFD)-fed mice were used as a DN model and were treated with or without Ipra for 6 weeks. Ipra treatment reduced urinary albumin excretion (UAE) and glomerular hypertrophy in HFD-fed mice. In the PRAT of Ipra-treated mice, adipocyte size was increased, and inflammation, fibrosis, and adipocyte death were suppressed. In conditioned medium made from PRAT (PRAT-CM) of Ipra-treated mice, the concentration of leptin was significantly lower than PRAT-CM of mice without Ipra treatment. Serum leptin concentration in renal vein positively correlated with UAE. PRAT-CM from HFD-fed mice showed greater cell proliferation signaling in mouse glomerular endothelial cells (GECs) than PRAT-CM from standard diet-fed mice via p38MAPK and leptin-dependent pathways, whose effects were significantly attenuated in PRAT-CM from Ipra-treated mice. These findings suggest that Ipra-induced PRAT expansion may play an important role in the improvement of DN in HFD-fed mice. In vitro experiments suggest that reduced PRAT-derived leptin by Ipra could inhibit GECs proliferation, possibly contributing to the suppression of DN development.
Highlights
Chronic kidney disease (CKD) is a common disease and is a risk factor for cardiovascular, cerebrovascular, and end-stage renal diseases (ESRD)
In addition to the amount of perirenal fat (PRAT), functional changes of PRAT including inflammation, and adipokines might help mediate diabetic nephropathy (DN); the amelioration of PRAT inflammation through genetic or exogenous inhibition of plasminogen activator inhibitor-1 (PAI-1) expression improved DN in high-fat diet (HFD)-fed mice [13]; an angiotensin II receptor blocker telmisartan inhibited leptin secretion from PRAT to ameliorate DN, accompanied with suppression of proliferative signaling in the kidney [14]
We found that Ipra treatment ameliorated DN in High-fat diet (HFD)-fed wild-type mice, accompanied by an expansion of PRAT
Summary
Chronic kidney disease (CKD) is a common disease and is a risk factor for cardiovascular, cerebrovascular, and end-stage renal diseases (ESRD) Metabolic diseases, such as diabetes mellitus, hypertension, obesity, and dyslipidemia, have been strongly associated with CKD development, with diabetic nephropathy (DN) being one of the most prevalent primary diseases in ESRD [1]. Sodium glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents that promote urinary glucose excretion by inhibiting glucose absorption at the proximal tubule. They have rapidly gained popularity because of their insulin-independent glycemic control activities and the ability to induce caloric loss and increase insulin sensitivity. Oxidative stress [7] and ectopic fat accumulation in the kidney [8] were reportedly involved in the development of DN
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