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

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) E 2 (PGE 2 ) signaling as a potential causative mechanism of albuminuria in GH. Method: For evaluation of the renal PGE 2 metabolic pathway, time-course lipidomic analysis of PGE 2 and its downstream metabolites 15-keto-PGE 2 and 13-14-dihydro-15-keto-PGE 2 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 PGE 2 and 15-keto-PGE 2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE 2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE 2 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 PGE 2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE 2 degradation. This study provides first insights into dynamic changes of the PGE 2 pathway that support a role of glomerular PGE 2 metabolism and signaling for early albuminuria manifestation in GH.