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