1. Deficiency of either P-glycoprotein or breast cancer resistance protein protect against acute kidney injury.
- Author
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Huls M, Schoeber JP, Verfaillie CM, Luttun A, Ulloa-Montoya F, Menke AL, van Bolderen LR, Woestenenk RM, Merkx GF, Wetzels JF, Russel FG, and Masereeuw R
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, ATP Binding Cassette Transporter, Subfamily G, Member 2, Acute Kidney Injury blood, Acute Kidney Injury urine, Animals, Bone Marrow Cells metabolism, Bone Marrow Transplantation, Female, Humans, Ischemia metabolism, Kidney blood supply, Kidney Function Tests, Mice, Mice, Knockout, Reperfusion Injury metabolism, Transduction, Genetic, ATP Binding Cassette Transporter, Subfamily B, Member 1 deficiency, ATP-Binding Cassette Transporters metabolism, Acute Kidney Injury metabolism, Kidney metabolism
- Abstract
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.
- Published
- 2010
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