Renal concentrating defect in mice lacking group IV cytosolic phospholipase A(2)

Eicosanoids regulate various cellular functions that are important in physi ological and pathophysiological processes. Arachidonic acid is released fro m membranes by phospholipase A(2) (PLA(2)) activity. Activated macrophages derived from mice lacking the 85-kDa group IV cytosolic PLA(2) (cPLA(2)) ha ve 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 creat inine, Na+, K+, and Ca2+ concentrations, glomerular filtration rate, and fr actional excretion of Na+ and K+ are not different in cPLA(2)(-/-) and cPLA (2)(-/-) mice. Maximal urinary concentration is lower in 48-h water-deprive d 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 def ect. 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. Howev er, 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 AQ P2, -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 m ay be related to abnormal trafficking and/or folding of AQP1 in the proxima l tubule, implicating cPLA(2) in these processes.