P-glycoprotein-deficient mice have proximal tubule dysfunction but are protected against ischemic renal injury.
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SourceKidney International. Supplement, 72, 10, (2007), pp. 1233-1241
Article / Letter to editor
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IMM - Institute for Molecules and Materials
Kidney International. Supplement
SubjectIGMD 3: Genomic disorders and inherited multi-system disorders; IGMD 9: Renal disorder; NCEBP 2: Evaluation of complex medical interventions; NCMLS 5: Membrane transport and intracellular motility; Synthetic Organic Chemistry; UMCN 2.2: Vascular medicine and diabetes; UMCN 5.4: Renal disorders
The multidrug resistance gene 1 product, P-glycoprotein (P-gp), is expressed in several excretory organs, including the apical membrane of proximal tubules. After inducing acute renal failure, P-gp expression is upregulated and this might be a protective function by pumping out toxicants and harmful products of oxidative stress. We characterized renal function of P-gp knockout mice and studied its consequences in renal ischemic damage. Compared with wild-type mice, knockout mice have a lower glomerular filtration rate and renal plasma flow. An augmented urinary excretion of sodium, numerous amino acids, calcium, glucose, and low molecular weight proteins was observed along with an increased diuresis. A higher lithium plasma clearance in the knockout mice suggested proximal tubular dysfunction. Electron microscopy showed mitochondrial abnormalities in proximal tubular cells that could account for decreased adenosine triphosphate levels in the cortex. After inducing ischemia, wild-type mice showed a decrease in creatinine clearance and severe proximal tubular necrosis. In contrast, knockout mice had no signs of tubular damage. Our data indicate that P-gp knockout mice have impaired renal function but are protected against ischemic renal injury.
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