Effects of ʟ-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy

Abstract

Introduction: In diabetic nephropathy (DN), mitochondrial dysfunction and leakage of mitochondrial DNA (mtDNA) are caused by the downregulation of superoxide dismutase 2 (SOD2). mtDNA induces the activation of Toll-like receptor (TLR) 9, which is present in macrophages (Mφs) and triggers their activation. Methods: We orally administered ʟ-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of ʟ-carnitine on kidney mtROS production, circulating mtDNA content, and kidney CD11b high/CD11b low Mφ functions. Results: In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11b low Mφs; both Mφ types showed enhanced TLR9 expression. ʟ-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11b low Mφs (p < 0.01), with improved SOD2 expression in the kidney (p < 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (p < 0.01), thereby lowering TNF-α production in CD11b high Mφs (p < 0.05) and ROS production by CD11b low Mφs (p < 0.01). Collectively, these changes alleviated DN symptoms. Discussion/Conclusion: The positive effects of ʟ-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.