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