Journal Article

Involvement of impaired carnitine-induced fatty acid oxidation in experimental and human diabetic kidney disease

Moriyama, Tomofumi, Taguchi, Kensei, Kaida, Yusuke, Yamagishi, Sho-ichi, Nakayama, Yosuke, Yamashita, Yuya, Ito, Sakuya, Yokota, Yunosuke, Tashiro, Kyoko, Fukami, Kei, Ohta, Keisuke, Kodama, Goh, Shinohara, Masami, Kubo, Saori

2025

Overview

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Kidney tubular cells have a high energy demand, dependent on fatty acid oxidation (FAO). Although carnitine is indispensable for FAO, the pathological role of carnitine deficiency in DKD is not fully understood. We showed here that ectopic lipid accumulation owing to impaired FAO increased in patients with DKD and inversely correlated with kidney function. Organic cation/carnitine transporter 2-deficient (OCTN2-deficient) mice exhibited systemic carnitine deficiency with increased renal lipid accumulation. Cell death and inflammation were induced in OCTN2-deficient, but not wild-type, tubular cells exposed to high salt and high glucose. Compared with Spontaneously Diabetic Torii (SDT) fatty rats, uninephrectomized SDT fatty rats fed with 0.3% NaCl showed higher lipid accumulation and increased urinary albumin excretion with kidney dysfunction and tubulointerstitial injury, all of which were ameliorated by l-carnitine supplementation via stimulating FAO and mitochondrial biogenesis. In our single-center randomized control trial with patients undergoing peritoneal dialysis, l-carnitine supplementation preserved residual renal function and increased urine volume, the latter of which was correlated with improvement of tubular injury. The present study demonstrates the pathological role of impairment of carnitine-induced FAO in DKD, suggesting that l-carnitine supplementation is a potent therapeutic strategy for this devastating disorder.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Adult / Animals / Cardiomyopathies / Carnitine / Carnitine - deficiency / Carnitine - metabolism / Carnitine - pharmacology / Cation/carnitine transporter / Cell biology / Cell death / Cholesterol / Creatinine / Diabetes / Diabetes mellitus / Diabetic Nephropathies - metabolism / Diabetic Nephropathies - pathology / Diabetic nephropathy / End-stage renal disease / Enzymes / Fatty acids / Fatty Acids - metabolism / Female / Glucose / Hemodialysis / Hemoglobin / High density lipoprotein / Homeostasis / Humans / Hyperammonemia - metabolism / Kidney - metabolism / Kidney - pathology / Kidney diseases / Lipid Metabolism / Lipids / Low density lipoprotein / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Middle Aged / Mitochondria / Muscular Diseases / Nephrology / Neutrophils / Oxidation / Oxidation-Reduction / Peritoneal dialysis / Plasma / Rats / Renal function / Rodents / Sodium chloride / Solute Carrier Family 22 Member 5 - deficiency / Solute Carrier Family 22 Member 5 - genetics / Solute Carrier Family 22 Member 5 - metabolism / Supplements