Yamaguchi Tamio, Lysecki Clara, Reid Ashleigh, Nagao Shizuko, Aukema Harold M
Department of Human Nutritional Sciences, University of Manitoba, W573 Duff Roblin Building, Winnipeg, MB, R3T 2N2, Canada.
Lipids. 2014 Jan;49(1):39-47. doi: 10.1007/s11745-013-3859-2. Epub 2013 Nov 1.
Nephronophthisis (NPHP) is a pediatric form of hereditary polycystic kidney disease (PKD), and is the leading cause of end stage renal disease in children. The pcy mouse is an orthologous model of human NPHP, with a mutation in the Nphp3 gene. Renal phospholipase A2, cyclooxygenase (COX) 1 and cyclic AMP are elevated in this model, suggesting that eicosanoid formation may be altered. In another type of PKD observed in the Han:SPRD-Cy rat, inhibition of eicosanoid production slows disease progression. If renal eicosanoids are similarly altered in NPHP, potential for pharmacologic intervention also may exist for this disorder. Therefore, renal fatty acids and eicosanoids were determined in pcy and normal mice at 15, 30 and 60 days of age by gas chromatography and HPLC-tandem mass spectrometry, respectively. Renal cysts in enlarged kidneys were observed in pcy mice by 15 days of age and increased over time. Renal phospholipid ARA levels were higher in pcy compared to normal mice at 15 and 30 days. Eicosanoid differences were observed starting at 30 days, when the COX products 6-keto-prostaglandin (PG) F1α, thromboxane B2 and PGE2 were higher in pcy compared to normal kidneys. Overall, total COX products were elevated at 30 and 60 days. In contrast, the levels of the lipoxygenase (LOX) products were not altered until 60 days of age and these were lower in pcy kidneys compared to normal. These findings suggest that altered eicosanoids play a role in NPHP, and that manipulating these levels with pharmacologic agents may have therapeutic potential.
肾单位肾痨（NPHP）是遗传性多囊肾病（PKD）的一种儿科形式，是儿童终末期肾病的主要原因。pcy小鼠是人类NPHP的直系同源模型，其Nphp3基因发生了突变。该模型中肾磷脂酶A2、环氧化酶（COX）1和环磷酸腺苷水平升高，提示类花生酸生成可能发生改变。在Han:SPRD-Cy大鼠中观察到的另一种PKD类型中，抑制类花生酸生成可减缓疾病进展。如果NPHP中肾类花生酸也发生类似改变，那么该疾病也可能存在药物干预的潜力。因此，分别通过气相色谱法和高效液相色谱-串联质谱法测定了15、30和60日龄pcy小鼠和正常小鼠的肾脂肪酸和类花生酸。到15日龄时，在pcy小鼠中观察到增大的肾脏中有肾囊肿，且囊肿数量随时间增加。在15日龄和30日龄时，pcy小鼠的肾磷脂花生四烯酸（ARA）水平高于正常小鼠。从30日龄开始观察到类花生酸差异，此时与正常肾脏相比，pcy小鼠的COX产物6-酮-前列腺素（PG）F1α、血栓素B2和前列腺素E2水平更高。总体而言，总COX产物在30日龄和60日龄时升高。相比之下，脂氧合酶（LOX）产物水平直到60日龄才发生改变，且与正常肾脏相比，pcy小鼠肾脏中的这些产物水平较低。这些发现表明，类花生酸改变在NPHP中起作用，用药物调节这些水平可能具有治疗潜力。
