Studies in Zebrafish and Rat Models Support Dual Blockade of EP2 and EP4 (Prostaglandin E ₂ Receptors Type 2 and 4) for Renoprotection in Glomerular Hyperfiltration and Albuminuria

Abstract

BACKGROUND: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Upregulation of COX2 (cyclooxygenase 2) and prostaglandin E 2 (PGE 2 ) was linked to podocyte damage in GH. We explored the potential renoprotective effects of either separate or combined pharmacological blockade of EP2 (PGE 2 receptor type 2) and EP4 (PGE 2 receptor type 4) in GH. METHODS: We conducted in vivo studies in a transgenic zebra fish model ( Tg[fabp10a:gc-EGFP] ) suitable for analysis of glomerular filtration barrier function and a genetic rat model with GH, albuminuria, and upregulation of PGE 2 . Similar pharmacological interventions and primary outcome analysis on albuminuria phenotype development were conducted in both model systems. RESULTS: Stimulation of zebra fish embryos with PGE 2 induced an albuminuria-like phenotype, thus mimicking the suggested PGE 2 effects on glomerular filtration barrier dysfunction. Both separate and combined blockade of EP2 and EP4 reduced albuminuria phenotypes in zebra fish and rat models. A significant correlation between albuminuria and podocyte damage in electron microscopy imaging was identified in the rat model. Dual blockade of both receptors showed a pronounced synergistic suppression of albuminuria. Importantly, this occurred without changes in arterial blood pressure, glomerular filtration rate, or tissue oxygenation in magnetic resonance imaging, while RNA sequencing analysis implicated a potential role of circadian clock genes. CONCLUSIONS: Our findings confirm a role of PGE 2 in the development of albuminuria in GH and support the renoprotective potential of combined pharmacological blockade of EP2 and EP4 receptors. These data support further translational research to explore this therapeutic option and a possible role of circadian clock genes.

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

“…In contrast, inhibition of EP2 and activation of EP4 has the strongest effect in decreasing albuminuria in a hyperfiltration-induced injury mouse model with unilaterally nephrectomy ( Srivastava et al, 2022 ). In the non-diabetic MWF rat model of CKD with GH, we showed a renoprotective effect of combined EP2/EP4 receptor inhibition of the COX2-PGE 2 -EP2/EP4 axis, since dual receptor blockade during onset of albuminuria development ameliorated albuminuria in this model, while systemic arterial blood pressure and GFR were not affected ( Kourpa et al, 2023 ). Taken together, EP2 and EP4 receptors are potential targets for therapeutical intervention in hyperfiltration-induced glomerular injury.…”

“…Effects of 15-keto-PGE 2 are mediated via EP2 and EP4 receptors in vitro and in vivo ( Endo et al, 2020 ; Kourpa et al, 2022 ). Previously, it has been shown that 15-keto-PGE 2 affects the glomerular morphology of zebrafish embryonic kidney ( Kourpa et al, 2023 ). However, the activity of PGE 2 degrading enzymes and thus the metabolic pathway of COX2-PGE 2 have not yet been implicated in renal physiology nor their potential contribution to the initiation and/or progression of CKD, i.e., albuminuria ( Nasrallah et al, 2014 ; Srivastava et al, 2014 ; Chen et al, 2018 ).…”

“…The glomerular hyperfiltration phenotype of MWF rats is due to an inherited nephron deficit with increased single nephron glomerular filtration rate and hemodynamically associated with dilatation of the afferent arteriole and normal glomerular capillary pressures ( Remuzzi et al, 1988 ; Fassi et al, 1998 ) Overall glomerular filtration in young rats, as studied in this report is similar to normal rat strains ( Rovira-Halbach et al, 1986 ; Fassi et al, 1998 ; van Es et al, 2011 ) MWF rats develop moderate hypertension, spontaneous albuminuria of early onset, and a congenital nephron deficit ( Schulz and Kreutz, 2012 ). Podocyte damage with focal and segmental foot process effacement and a reduced podocyte number were early found in young adult MWF animals ( Ijpelaar et al, 2008 ; Kourpa et al, 2023 ). With increasing age further significant structural renal abnormalities such as glomerulosclerosis and renal interstitial fibrosis with progressive albuminuria development were observed ( Schulz and Kreutz, 2012 ).…”

Complementary roles of EP2 and EP4 receptors in malignant glioma

“…If this is the case, blocking EP 2 and EP 4 alone may not be able to effectively impair tumour growth in GBM patients. To address this concern, future study should be also directed to explore the anti-tumour effects of simultaneously blocking both EP 2 and EP 4 receptors on GBM tumour growth by a dual antagonist, for example TPST-1495, which is currently under clinical trial for treatment of various solid cancers (https://clinicaltrials.gov/ct2/show/NCT04344795), or by combined treatment with separate EP 2 and EP 4 antagonists as recently reported (Kourpa et al, 2023;Thumkeo et al, 2022).…”