Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2).
Eicosanoids regulate various cellular functions that are important in physiological and pathophysiological processes. Arachidonic acid is released from membranes by phospholipase A(2) (PLA(2)) activity. Activated macrophages derived from mice lacking the 85-kDa group IV cytosolic PLA(2) (cPLA(2)) have a markedly reduced release of prostaglandin E(2) and leukotrienes B(4) and C(4). Under basal conditions and after furosemide, urinary prostaglandin E(2) excretion is reduced in cPLA(2)-knockout (cPLA(2)(-/-)) mice. Serum creatinine, Na(+), K(+), and Ca(2+) concentrations, glomerular filtration rate, and fractional excretion of Na(+) and K(+) are not different in cPLA(2)(-/-) and cPLA(2)(+/+) mice. Maximal urinary concentration is lower in 48-h water-deprived cPLA(2)(-/-) mice compared with cPLA(2)(+/+) animals (1,934 +/- 324 vs. 3,541 +/- 251 mmol/kgH(2)O). Plasma osmolality is higher (337 +/- 5 vs. 319 +/- 3 mmol/kgH(2)O) in cPLA(2)(-/-) mice that lose a greater percentage of their body weight (20 +/- 2 vs. 13 +/- 1%) compared with cPLA(2)(+/+) mice after water deprivation. Vasopressin does not correct the concentrating defect. There is progressive reduction in urinary osmolality with age in cPLA(2)(-/-) mice. Membrane-associated aquaporin-1 (AQP1) expression, identified by immunocytochemical techniques, is reduced markedly in proximal tubules of older cPLA(2)(-/-) animals but is normal in thin descending limbs. However, Western blot analysis of kidney cortical samples revealed an equivalent AQP1 signal intensity in cPLA(2)(+/+) and cPLA(2)(-/-) animals. Young cPLA(2)(-/-) mice have normal proximal tubule AQP1 staining. Collecting duct AQP2, -3, and -4 were normally expressed in the cPLA(2)(-/-) mice. Thus mice lacking cPLA(2) develop an age-related defect in renal concentration that may be related to abnormal trafficking and/or folding of AQP1 in the proximal tubule, implicating cPLA(2) in these processes.
Downey
P
P
Medical and Anesthesia Services, Massachusetts General Hospital, Charlestown, 02129, USA.
Sapirstein
A
A
O'Leary
E
E
Sun
T X
TX
Brown
D
D
Bonventre
J V
JV
D000818:Animals; D051398:Aquaporin 1; D051399:Aquaporin 2; D051400:Aquaporin 3; D051401:Aquaporin 4; D051403:Aquaporin 6; D020346:Aquaporins / Q000032:analysis / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000378:metabolism; D004326:Drinking; D004435:Eating; D005260:Female; D005455:Fluorescent Antibody Technique; D054513:Group IV Phospholipases A2; D007671:Kidney Concentrating Ability / Q000187:drug effects / Q000502:physiology*; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008138:Loop of Henle / Q000737:chemistry / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009994:Osmolar Concentration; D010741:Phospholipases A / Q000235:genetics* / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism; D014667:Vasopressins / Q000494:pharmacology; D014868:Water Deprivation / Q000502:physiology
C496021:Aqp1 protein, mouse; C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; C496031:Aqp4 protein, mouse; D051399:Aquaporin 2; D051401:Aquaporin 4; D051403:Aquaporin 6; D020346:Aquaporins; C516390:Pla2g4a protein, mouse; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D051398:Aquaporin 1; D051400:Aquaporin 3; D007975:Leukotriene B4; D017997:Leukotriene C4; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D015232:Dinoprostone