Kaiser-Graf Debora, Schulz Angela, Mangelsen Eva, Rothe Michael, Bolbrinker Juliane, Kreutz Reinhold
Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Lipidomix GmbH, Berlin, Germany.
Front Netw Physiol. 2023 Dec 22;3:1271042. doi: 10.3389/fnetp.2023.1271042. eCollection 2023.
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) E (PGE) signaling as a potential causative mechanism of albuminuria in GH. For evaluation of the renal PGE metabolic pathway, time-course lipidomic analysis of PGE and its downstream metabolites 15-keto-PGE and 13-14-dihydro-15-keto-PGE 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). Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE and 15-keto-PGE were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE 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. Our data reveal glomerular dysregulation of the PGE metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE degradation. This study provides first insights into dynamic changes of the PGE pathway that support a role of glomerular PGE metabolism and signaling for early albuminuria manifestation in GH.
肾小球高滤过（GH）是高血压患者蛋白尿发生发展的重要机制。慕尼黑Wistar Frömter（MWF）大鼠是一种慢性肾脏病（CKD）的非糖尿病模型，由于遗传性肾单位数量减少导致GH，进而出现自发性蛋白尿和足细胞损伤。在MWF大鼠中，我们确定前列腺素（PG）E（PGE）信号传导是GH中蛋白尿的潜在致病机制。为了评估肾脏PGE代谢途径，通过液相色谱电喷雾电离串联质谱法（LC/ESI-MS/MS），对MWF大鼠和抗蛋白尿自发性高血压大鼠（SHR）的尿液、血浆和肾脏组织进行了PGE及其下游代谢产物15-酮-PGE和13-14-二氢-15-酮-PGE的时间进程脂质组学分析。脂质组学分析显示，在蛋白尿发展的时间进程中，血浆PGs没有失调，而与抗蛋白尿SHR相比，MWF大鼠肾小球中的PGE和15-酮-PGE水平显著升高。总体而言，肾小球中PGE的平均水平比相应的15-酮-PGE水平高150倍。与SHR相比，出现蛋白尿的MWF大鼠中15-羟基前列腺素脱氢酶（15-PGDH）的肾小球代谢率显著降低，而前列腺素还原酶（PTGRs）的代谢率显著升高。我们的数据揭示了GH中蛋白尿发展过程中PGE代谢的肾小球失调，这至少部分是由于PGE降解减少所致。本研究首次深入了解了PGE途径的动态变化，这些变化支持肾小球PGE代谢和信号传导在GH早期蛋白尿表现中的作用。
