Human adipose tissue-derived mesenchymal stem cells protect kidneys from cisplatin nephrotoxicity in rats.
Cisplatin has multiple cellular targets and modes of action that lead to nephrotoxicity. This suggests novel therapies that act at multiple cisplatin target sites may be effective. We tested whether human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) can affect multiple target sites and protect against cisplatin-induced kidney damage. Rats were divided into four groups: control, infused with Ad-MSCs, injected with cisplatin, and cisplatin followed by infusion of Ad-MSCs. Animal survival and renal function were decreased and histological damage was increased in cisplatin-treated rats at day 3. Infusion of Ad-MSCs ameliorated renal dysfunction and tissue injury caused by cisplatin, leading to increased survival. Apoptotic cell death in the kidney was significantly reduced by infusion of Ad-MSCs. Activation of p53, JNK, and ERK and the expression of inflammation-related molecules were also decreased in the kidney that received Ad-MSCs. Very few Ad-MSCs were detected in the kidney. Conditioned medium from cultured Ad-MSCs had renal-protective functions in vivo and in vitro. Renal dysfunction and tissue damage caused by cisplatin were significantly reduced in rats treated with Ad-MSCs-conditioned medium. The viability of cultured renal proximal tubular cells exposed to cisplatin was also improved by coculture with Ad-MSCs or with conditioned medium. Release of proinflammatory mediators induced by cisplatin was inhibited in coculture with Ad-MSCs. Our results show that human Ad-MSCs exert a paracrine-protective effect on cisplatin nephrotoxicity at multiple target sites and suggest that human Ad-MSCs might be a new therapeutic approach for patients with acute kidney injury.
Clinical Research Institute, Gyeongsang National University Hospital, Gyeongsang National University, Gyeongnam, Republic of Korea.
Jin Hyun
JH
Kim
Dong Jun
DJ
Park
Ji Chul
JC
Yun
Myeong Hee
MH
Jung
Hee Dong
HD
Yeo
Hyun-Jung
HJ
Kim
Dong Wook
DW
Kim
Jung Ill
JI
Yang
Gyeong-Won
GW
Lee
Sang-Ho
SH
Jeong
Gu Seob
GS
Roh
Se-Ho
SH
Chang
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D023421:Models, Animal; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin