Introduction Diabetic nephropathy is a rapidly growing cause
Diabetic nephropathy is a rapidly growing cause of end-stage renal disease . Glomerular, tubular and vascular toxicity resulting from hyperglycemia (glucotoxicity) have been evaluated extensively at the molecular level as contributing factors for diabetic nephropathy [, , ]. 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) [, , ]. 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 . 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 .
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 . Evidence from human and animal model studies suggests that accumulation of lipid and its metabolites in tissues, including the kidney, causes lipotoxicity . Of the lipids that accrue, sphingolipids, including, ceramides are particularly detrimental to tissue . Ceramides are abundant in the kidney and regulate diverse cellular events including differentiation, growth arrest, and apoptosis [, , ]. 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 . 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  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 . 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 .
Materials and Methods
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  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.