Deficiency of either P-glycoprotein or breast cancer resistance protein protect against acute kidney injury.
The kidney has a high capacity to regenerate after ischemic injury via several mechanisms, one of which involves bone marrow-derived (stem) cells. The ATP binding cassette transporters, P-glycoprotein and breast cancer resistance protein, are determinants for the enriched stem and progenitor cell fraction in bone marrow. Because they are upregulated after acute kidney injury, we hypothesized that both efflux pumps may play a role in protecting against renal injury. Surprisingly, transporter-deficient mice were protected against ischemia-induced renal injury. To further study this, bone marrow from irradiated wild-type mice was reconstituted by bone marrow from wild-type, P-glycoprotein- or breast cancer resistance protein-deficient mice. Four weeks later, kidney injury was induced and its function evaluated. Significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow. A gender mismatch study suggested that cell fusion of resident tubular cells with bone marrow cells was unlikely. Renal function analyses indicated an absence of renal damage following ischemia-reperfusion in animals transplanted with transporter-deficient bone marrow. When wild-type bone marrow was transplanted in breast cancer resistance protein-deficient mice this protection is lost. Furthermore, we demonstrate that transporter-deficient bone marrow contained significantly more monocytes, granulocytes, and early outgrowth endothelial progenitor cells.
Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Miriam
M
Huls
Joost P H
JP
Schoeber
Catherine M
CM
Verfaillie
Aernout
A
Luttun
Fernando
F
Ulloa-Montoya
Aswin L
AL
Menke
Lars R
LR
van Bolderen
Rob M
RM
Woestenenk
Gerard F M
GF
Merkx
Jack F M
JF
Wetzels
Frans G M
FG
Russel
Rosalinde
R
Masereeuw
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D005260:Female; D006801:Humans; D007511:Ischemia / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism*; D007677:Kidney Function Tests; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000378:metabolism; D014161:Transduction, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse