AUTHOR=Kaiser-Graf Debora , Schulz Angela , Mangelsen Eva , Rothe Michael , Bolbrinker Juliane , Kreutz Reinhold 

TITLE=Tissue lipidomic profiling supports a mechanistic role of the prostaglandin E2 pathway for albuminuria development in glomerular hyperfiltration

JOURNAL=Frontiers in Network Physiology

VOLUME=3

YEAR=2023

URL=https://www.frontiersin.org/journals/network-physiology/articles/10.3389/fnetp.2023.1271042

DOI=10.3389/fnetp.2023.1271042

ISSN=2674-0109

ABSTRACT=<p><bold>Background:</bold> 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<sub>2</sub> (PGE<sub>2</sub>) signaling as a potential causative mechanism of albuminuria in GH.</p><p><bold>Method:</bold> For evaluation of the renal PGE<sub>2</sub> metabolic pathway, time-course lipidomic analysis of PGE<sub>2</sub> and its downstream metabolites 15-keto-PGE<sub>2</sub> and 13-14-dihydro-15-keto-PGE<sub>2</sub> 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).</p><p><bold>Results:</bold> Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE<sub>2</sub> and 15-keto-PGE<sub>2</sub> were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE<sub>2</sub> levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE<sub>2</sub> 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.</p><p><bold>Conclusion:</bold> Our data reveal glomerular dysregulation of the PGE<sub>2</sub> metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE<sub>2</sub> degradation. This study provides first insights into dynamic changes of the PGE<sub>2</sub> pathway that support a role of glomerular PGE<sub>2</sub> metabolism and signaling for early albuminuria manifestation in GH.</p>