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Abstract：
Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH. Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively. Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.
摘要：
背景：肾小球滤过（GH）是高血压蛋白尿发展的重要机制。慕尼黑WistarFrömter（MWF）大鼠是慢性肾脏疾病（CKD）的非糖尿病模型，由于遗传性低肾单位数导致自发性蛋白尿和足细胞损伤，因此具有GH。在MWF大鼠中，我们确定前列腺素（PG）E2（PGE2）信号是GH中蛋白尿的潜在致病机制。方法：为了评估肾脏PGE2代谢途径，在尿液中进行PGE2及其下游代谢物15-酮-PGE2和13-14-二氢-15-酮-PGE2的时程脂质组学分析，采用液相色谱-电喷雾串联质谱(LC/ESI-MS/MS)检测MWF大鼠和抗蛋白尿自发性高血压大鼠(SHR)的血浆和肾组织。结果：脂质组学分析显示，在蛋白尿发展的过程中，血浆PG没有失调，而与耐蛋白尿的SHR相比，MWF中PGE2和15-keto-PGE2的肾小球水平显着升高。总的来说,肾小球中的平均PGE2水平比相应的15-酮-PGE2水平高多达150倍。15-羟基前列腺素脱氢酶（15-PGDH）的肾小球代谢比率显着降低，虽然前列腺素还原酶（PTGRs）的代谢比率在MWF大鼠中明显高于SHR，分别。结论：我们的数据揭示了GH蛋白尿发展过程中PGE2代谢的肾小球失调，至少部分地由减少的PGE2降解产生。这项研究为PGE2通路的动态变化提供了初步见解，该通路支持肾小球PGE2代谢和信号在GH中早期白蛋白尿表现中的作用。
