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P-glycoprotein-deficient mice have proximal tubule dysfunction but are protected against ischemic renal injury

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Author: Huls, M. · Kramers, C. · Levtchenko, E.N. · Wilmer, M.J.G. · Dijkman, H.B.P.M. · Kluijtmans, L.A.J. · Hoorn, J.W.A. van der · Russel, F.G.M. · Masereeuw, R.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Kidney International, 10, 72, 1233-1241
Identifier: 280079
doi: doi:/10.1038/sj.ki.5002522
Keywords: Biology · ABC transporter · Drug transporter · Ischemia-reperfusion · Kidney dysfunction · ABC transporter · adenosine triphosphate · amino acid · calcium · creatinine · glucose · glycoprotein P · lithium · protein · sodium · amino acid urine level · animal model · animal tissue · calcium excretion · controlled study · creatinine clearance · diuresis · electron microscopy · glomerulus filtration rate · glucosuria · kidney blood flow · kidney cortex · kidney injury · kidney ischemia · kidney proximal tubule · kidney tubule necrosis · knockout mouse · oxidative stress · plasma clearance · priority journal · protein expression · protein function · sodium excretion · upregulation · urinary excretion · Amino Acids · Animals · Calcium · Diuresis · Fluorescent Antibody Technique · Glomerular Filtration Rate · Glycosuria · Immunohistochemistry · Ischemia · Kidney Failure, Acute · Kidney Tubules, Proximal · Male · Mice · Mice, Inbred Strains · Mice, Knockout · Mitochondria · P-Glycoprotein · Proteinuria · Renal Circulation · Sodium

Abstract

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. © 2007 International Society of Nephrology. Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; amino acid, 65072-01-7; calcium, 7440-70-2; creatinine, 19230-81-0, 60-27-5; glucose, 50-99-7, 84778-64-3; lithium, 7439-93-2; protein, 67254-75-5; sodium, 7440-23-5; Amino Acids; Calcium, 7440-70-2; P-Glycoprotein; Sodium, 7440-23-5