Introduction Diabetic nephropathy is a rapidly growing cause

Introduction Diabetic nephropathy is a rapidly growing cause of end-stage renal disease [1]. Glomerular, tubular and vascular toxicity resulting from hyperglycemia (glucotoxicity) have been evaluated extensively at the molecular level as contributing factors for diabetic nephropathy [[1], [2], [3]]. Recently, many studies of lipid metabolism in diabetic nephropathy have been reported. Lipotoxicity is related to lipid-induced changes in intracellular signaling pathways, and is the key to the pathogenesis of chronic kidney disease (CKD) [[4], [5], [6]]. Lipotoxicity in glomeruli is also involved in the initiation of glomerular damage related to obesity and type 2 diabetes mellitus (T2DM) [7,8]. Furthermore, lipotoxicity has a negative impact on eNOS gene expression and eNOS catalytic activity, resulting in inflammation, oxidative stress, or insulin resistance in endothelial cells [5]. However, the mechanisms for dyslipidemia in diabetic nephropathy are multifactorial and complex. Plasma lipid profiles change substantially as the nephropathy progresses. Diabetes per se is thus a principal cause of plasma lipid abnormalities [9]. Oxidation of dysregulated fatty Adrucil has been connected with an effector pathway in the pathophysiology of diabetes [8,10]. An imbalance between circulating and cytosolic fatty acid levels resulting in immoderate intracellular accumulation of fatty acids and their derivatives, such as ceramides, underlies insulin resistance in diabetes [8,11]. Excessive ectopically accumulated lipids in non-adipose tissues may occur with high plasma nonesterified fatty acids (NEFAs) or triacylglycerols [12]. Evidence from human and animal model studies suggests that accumulation of lipid and its metabolites in tissues, including the kidney, causes lipotoxicity [5]. Of the lipids that accrue, sphingolipids, including, ceramides are particularly detrimental to tissue [13]. Ceramides are abundant in the kidney and regulate diverse cellular events including differentiation, growth arrest, and apoptosis [[14], [15], [16]]. Ceramide consists of N-acetylated (14–26 carbons) sphingosine (16–18 carbons) and is produced primarily from the hydrolysis of sphingomyelin catalyzed by sphingomyelinase [14,17]. Lowering the accumulation of ceramide can ameliorate insulin resistance, steatohepatitis, and other metabolic disorders [13,18]. Recently, Holland et al. showed that adiponectin potently stimulates a ceramidase activity associated with its two receptors, adiponectin receptor (AdipoR)1 and (AdipoR)2, and enhances ceramide catabolism and formation of its anti-apoptotic metabolite, S1P, independently of AMPK [19]. The pleiotropic actions of adiponectin have been linked to the ceramidase activity in crude cell lysates, and both AdipoR1 and AdipoR2 possess intrinsic ceramidase activity based on their crystal structures [20] and an increase of ceramidase activity with overexpression of adiponectin in mice improves ceramide-dependent lipotoxicity [13,19]. We have previously reported that PPARα deficiency appears to aggravate the severity of diabetic nephropathy through an increase in extracellular matrix formation, inflammation, and circulating NEFAs and triacylglycerol concentrations [21]. Afterward, we have shown that resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–sirtuin (SIRT)1–peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1)α signal pathway in db/db mice [22].
Materials and Methods
Results
Discussion The current study showed that AdipoRon-fed db/db mice had decreased albuminuria and lipid accumulation in the kidney related to the increased expression of AdipoR1/R2 in the kidney. Consistent upregulation of phospho-Thr172 AMPK, PPARα, phospho-Ser473 Akt, phospho-Ser79 ACC, and phospho-Ser1177 eNOS and downregulation of protein phosphatase 2A, SREBP-1c, and iNOS were demonstrated in AdipoRon-treated db/db mice. AdipoRon reduced ceramide levels by activation of acid ceramidase, which hydrolyzes ceramide to form sphingosine leading to an increase in S1P, a potent inhibitor of apoptosis [28] which resulted in recovered ceramide to S1P ratio in the kidney, In GECs and podocytes, AdipoRon treatment markedly decreased palmitate-induced lipotoxicity through the AdipoR1-AMPK and AdipoR2–PPARα pathways, respectively, which ultimately ameliorated oxidative stress and apoptosis.