Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

• Published in: Diabetes & metabolism journal Vol. 44; no. 4; pp. 581 - 591
• Main Authors: Woo, Chang-Yun, Baek, Ji Yeon, Kim, Ah-Ram, Hong, Chung Hwan, Yoon, Ji Eun, Kim, Hyoun Sik, Yoo, Hyun Ju, Park, Tae-Sik, Kc, Ranjan, Lee, Ki-Up, Koh, Eun Hee
• Format: Journal Article
• Language: English
• Published: Korean Diabetes Association 01.08.2020; 대한당뇨병학회
• Subjects: ceramides; diabetic nephropathies; mitochondria; Original; podocytes; reactive oxygen species; thermozymocidin; 내과학
• ISSN: 2233-6079; 2233-6087
• DOI: 10.4093/dmj.2019.0063

BACKGROUNDCeramides 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. METHODSWe 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. RESULTSOLETF 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. CONCLUSIONWe 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.