Medizinische Universität Graz - Research portal
Selected Publication:
Aringer, I.
The Role of Prostaglandin E2 Receptor 4 (EP4) in the Murine Model of Nephrotoxic Serum Nephritis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2019. pp. 121
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- Authors Med Uni Graz:
- Advisor:
- Eller Kathrin
- Eller Philipp
- Heinemann Akos
- Strobl Herbert
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- Abstract:
- The lipid molecule and cyclooxygenase (COX) product prostaglandin E2 (PGE2) acts on four different G protein-coupled receptors namely EP1 to 4. EP4 receptors are expressed on different immune cells, resident kidney cells (epithelial cells of the glomerulus, mesangial cells, afferent arteriole, collecting duct, proximal and distal tubular cells) and endothelial cells. These cells play a crucial role in the pathophysiology of immune-mediated diseases such as glomerulonephritis. Thus, selectively targeting the receptors of PGE2 (E-type prostanoid receptors) might be an attractive new therapeutic option in the treatment of glomerulonephritis. Therefore, we tested EP4 receptor agonists and antagonists in a murine model of nephrotoxic serum nephritis (NTS), which reflects immune-complex nephritis in humans. In vivo treatment with two different doses of an EP4 agonist ONO AE1-329 [280 or 1000 μg/kg bw/day], antagonist ONO AE3-208 [10 mg/kg bw/day] or vehicle was performed for 10 or 14 days of NTS. EP4 was stimulated or blocked on murine distal convoluted tubular epithelial cells in vitro. In vivo, the higher dose of the EP4 agonist led to an improved NTS phenotype due to recurrent hypotensive episodes resulting in ischemic preconditioning. This was accompanied by decreased renal infiltration of immune cells. Furthermore, it significantly increased tubular cell proliferation in vivo and in vitro. These effects were dose-dependent since treatment with the low-dose agonist resulted in less pronounced episodes of hypotension and a comparable phenotype to vehicle controls. Interestingly, EP4 antagonist treatment did not have any effects on blood pressure and significantly improved the NTS phenotype. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. It decreased tubular chemokine (C-X-C motif) ligands CXCL1 and CXCL5 expression and reduced interstitial neutrophil influx into the kidney. Taken together, the hemodynamic effects of EP4 agonism limit its therapeutic use in NTS. In contrast, EP4 antagonism has no effect on blood pressure and improves the NTS phenotype, most likely by decreasing CXCL1 and -5 production in tubular cells and thereby reducing renal neutrophil infiltration.