Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway

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• 作者：Xiaojiang Tang^a ; ¹ ; ^{river-t@126.com" class="auth_mail" title="E-mail the corresponding author} ; Jinqiu Zhu^b ; ¹ ; Zhiyong Zhong^a ; Minhui Luo^a ; Guangxian Li^a ; Zhihong Gong^b ; Chenzi Zhang^a ; Fan Fei^a ; Xiaolin Ruan^c ; Jinlin Zhou^d ; Gaofeng Liu^e ; Guoding Li^a ; James Olson^b ; ^f ; Xuefeng Ren^a ; ^b ; ^f ; ^{xuefengr@buffalo.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cadmium decorporation ; Cadmium induced renal dysfunction ; Chelating agent ; GMDTC ; Renal glucose reabsorption pathway
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2016
• 出版时间：15 August 2016
• 年：2016
• 卷：305
• 期：Complete
• 页码：143-152
• 全文大小：1145 K

文摘

Chronic exposure to cadmium compounds (Cd^2 +) is one of the major public health problems facing humans in the 21st century. Cd^2 + in the human body accumulates primarily in the kidneys which leads to renal dysfunction and other adverse health effects. Efforts to find a safe and effective drug for removing Cd^2 + from the kidneys have largely failed. We developed and synthesized a new chemical, sodium (S)-2-(dithiocarboxylato((2S,3R,4R,5R)-2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio) butanoate (GMDTC). Here we report that GMDTC has a very low toxicity with an acute lethal dose (LD50) of more than 10,000 mg/kg or 5000 mg/kg body weight, respectively, via oral or intraperitoneal injection in mice and rats. In in vivo settings, up to 94% of Cd^2 + deposited in the kidneys of Cd^2 +-laden rabbits was removed and excreted via urine following a safe dose of GMDTC treatment for four weeks, and renal Cd^2 + level was reduced from 12.9 μg/g to 1.3 μg/g kidney weight. We observed similar results in the mouse and rat studies. Further, we demonstrated both in in vitro and in animal studies that the mechanism of transporting GMDTC and GMDTC-Cd complex into and out of renal tubular cells is likely assisted by two glucose transporters, sodium glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2). Collectively, our study reports that GMDTC is safe and highly efficient in removing deposited Cd^2 + from kidneys assisted by renal glucose reabsorption system, suggesting that GMDTC may be the long-pursued agent used for preventive and therapeutic purposes for both acute and chronic Cd^2 + exposure.