Downey P, Sapirstein A, O'Leary E, Sun T X, Brown D, Bonventre J V
Medical and Anesthesia Services, Massachusetts General Hospital, Charlestown, 02129, USA.
Am J Physiol Renal Physiol. 2001 Apr;280(4):F607-18. doi: 10.1152/ajprenal.2001.280.4.F607.
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.
类花生酸调节各种细胞功能，这些功能在生理和病理生理过程中很重要。花生四烯酸通过磷脂酶A2（PLA2）的活性从细胞膜释放。缺乏85 kDa的IV型胞质PLA2（cPLA2）的小鼠来源的活化巨噬细胞中，前列腺素E2以及白三烯B4和C4的释放明显减少。在基础条件下以及给予呋塞米后，cPLA2基因敲除（cPLA2-/-）小鼠的尿前列腺素E2排泄减少。cPLA2-/-和cPLA2+/+小鼠的血清肌酐、Na+、K+和Ca2+浓度、肾小球滤过率以及Na+和K+的分数排泄没有差异。与cPLA2+/+动物相比，48小时缺水的cPLA2-/-小鼠的最大尿浓缩能力较低（分别为1,934±324和3,541±251 mmol/kgH2O）。缺水后，cPLA2-/-小鼠的血浆渗透压更高（分别为337±5和319±3 mmol/kgH2O），其体重减轻的百分比更大（分别为20±2和13±1%）。血管加压素不能纠正浓缩缺陷。随着年龄增长，cPLA2-/-小鼠的尿渗透压逐渐降低。通过免疫细胞化学技术鉴定，膜相关水通道蛋白1（AQP1）的表达在老年cPLA2-/-动物的近端小管中明显减少，但在细降支中正常。然而，对肾皮质样本的蛋白质印迹分析显示，cPLA2+/+和cPLA2-/-动物的AQP1信号强度相当。年轻的cPLA2-/-小鼠近端小管AQP1染色正常。集合管AQP2、-3和-4在cPLA2-/-小鼠中正常表达。因此，缺乏cPLA2的小鼠会出现与年龄相关的肾脏浓缩功能缺陷，这可能与近端小管中AQP1的异常转运和/或折叠有关，提示cPLA2参与了这些过程。
