Effects of L-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy
Seigo Ito, Masahiro Nakashima, Takuya Ishikiriyama, Hiroyuki Nakashima, Akira Yamagata, Toshihiko Imakiire, Manabu Kinoshita, Shuhji Seki, Hiroo Kumagai, Naoki Oshima
Abstract
<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> We orally administered L-carnitine, which exerts protective effects on the mitochondria, to obesity-induced DN (db/db) mice for 8 weeks. We then investigated the effects of L-carnitine on kidney mitochondrial reactive oxygen species (mtROS) production, circulating mtDNA content, and kidney CD11b<sup>high</sup>/CD11b<sup>low</sup> Mφ functions. <b><i>Results:</i></b> In db/db mice, mtROS production increased in proximal tubular cells and kidney CD11b<sup>low</sup> Mφs; both Mφ types showed enhanced TLR9 expression. L-Carnitine treatment suppressed mtROS production in both proximal tubular cells and CD11b<sup>low</sup> Mφs (<i>p</i> &#x3c; 0.01), with improved SOD2 expression in the kidney (<i>p</i> &#x3c; 0.01), decreased circulating mtDNA content, and reduced albuminuria. Moreover, it suppressed Mφ infiltration into kidneys and reduced TLR9 expression in Mφs (<i>p</i> &#x3c; 0.01), thereby lowering tumor necrosis factor-α production in CD11b<sup>high</sup> Mφs (<i>p</i> &#x3c; 0.05) and ROS production by CD11b<sup>low</sup> Mφs (<i>p</i> &#x3c; 0.01). Collectively, these changes alleviated DN symptoms. <b><i>Conclusion:</i></b> The positive effects of L-carnitine on DN suggest its potential as a novel therapeutic agent against obesity-linked DN.