Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

Abstract

Background: Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy. Methods: We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control-or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes. Results: OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity. Conclusion: We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

“…Additionally, treatment with berberine improved renal injury in STZ-induced diabetic rats via downregulation of S1PR2 [ 105 ] and the use of the S1PR2 specific antagonist LTE-013 showed improved insulin resistance in human and rat hepatocytes [ 106 ], suggesting the possibility that S1PR2 inhibition may prove useful for the treatment of diabetes and its related complications. Another study demonstrated that inhibition of ceramide accumulation with myriocin in Otsuka Long Evans Tokushima fatty rats and HFD-fed mice ameliorates albuminuria and histologic features of DKD [ 107 ]. Finally, our studies demonstrated that exogenous C1P treatment or podocyte-specific inhibition of SMDP3Lb results in reduced proteinuria, improves renal outcome and restores insulin receptor signaling in diabetic db/db mice [ 6 ].…”

Saturated fatty acids induce insulin resistance in podocytes through inhibition of IRS1 via activation of both IKKβ and mTORC1

“…Both endogenous and exogenous ceramides can contribute to the insulin resistance phenomenon. Previous studies reported that administration of myriocin blocked homocysteine- and high-fat diet-induced glomerular injury in the kidney 39 , 40 . In addition, palmitate exposure in cultured podocytes led to increased ceramide production 40 .…”

“…Previous studies reported that administration of myriocin blocked homocysteine- and high-fat diet-induced glomerular injury in the kidney 39 , 40 . In addition, palmitate exposure in cultured podocytes led to increased ceramide production 40 . Inhibition of ceramide synthesis using fumonosin B1 or myriocin partially prevented palmitate-induced inhibition of glucose uptake following insulin stimulation 41 .…”

Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools

“…Such myriocin-induced, hormesislike stress responses have been demonstrated in Caenorhabditis elegans [86] and recently Myr treatment, along with RNAi knockdown or mutation of the serine palmitoyltransferase gene, were shown to increase lifespan in C. elegans [87]. Finally, a growing body of data show that Myr treatment reduces the severity of age-related diseases in mice and rats: low dose Myr treatment lowers atherosclerosis and cardiac impairment [88][89][90][91] and reduces risk factors for metabolic syndrome, obesity, diabetes and cancer [92][93][94][95][96]. Myr also reduces amyloid beta and tau hyperphosphorylation in a mouse model of Alzheimer's disease [97] and has therapeutic effects on other neurodegenerative diseases [98,99].…”