Mobilization and removing of cadmium from kidney by GMDTC utilizing renal glucose reabsorption pathway.
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 10,000mg/kg or 5000mg/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 12.9μg/g to 1.3μg/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.
Guangdong Medical Laboratory Animal Center, China. Electronic address: river-t@126.com.
Xiaojiang
X
Tang
Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY, USA.
Jinqiu
J
Zhu
Guangdong Medical Laboratory Animal Center, China.
Zhiyong
Z
Zhong
Guangdong Medical Laboratory Animal Center, China.
Minhui
M
Luo
Guangdong Medical Laboratory Animal Center, China.
Guangxian
G
Li
Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY, USA.
Zhihong
Z
Gong
Guangdong Medical Laboratory Animal Center, China.
Chenzi
C
Zhang
Guangdong Medical Laboratory Animal Center, China.
Fan
F
Fei
Guangdong Poison Control Center, China.
Xiaolin
X
Ruan
Golden Health (Foshan) Technology Co., Ltd, China.
Jinlin
J
Zhou
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, China.
Gaofeng
G
Liu
Guangdong Medical Laboratory Animal Center, China.
Guoding
G
Li
Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY, USA; Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY, USA.
James
J
Olson
Guangdong Medical Laboratory Animal Center, China; Department of Epidemiology and Environmental Health, The State University of New York, Buffalo, NY, USA; Department of Pharmacology and Toxicology, The State University of New York, Buffalo, NY, USA. Electronic address: xuefengr@buffalo.edu.
Xuefeng
X
Ren
D000818:Animals; D002104:Cadmium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D005947:Glucose / Q000378:metabolism; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D023382:Toxicity Tests, Acute; D059550:Toxicity Tests, Subchronic
C000619492:2-(dithiocarboxylato(2,3,4,5,6 pentahydroxyhexyl)amino)-4-(methylthio)butanoic acid; D002614:Chelating Agents; D051273:Glucose Transporter Type 2; C495680:SLC2A2 protein, human; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D002104:Cadmium; D008715:Methionine; D005947:Glucose; D005944:Glucosamine
Cadmium decorporation; Cadmium induced renal dysfunction; Chelating agent; GMDTC; Renal glucose reabsorption pathway