Agonism of Prostaglandin E2 Receptor 4 Ameliorates Tubulointerstitial Injury in Nephrotoxic Serum Nephritis in Mice.

Ida Aringer,Katharina Artinger,Thomas Bärnthaler,Corinna Schabhüttl,Philipp Eller,Andrijana Kirsch,Marion Pollheimer,Akos Heinemann,Agnes A Mooslechner,Alexander R Rosenkranz,Kathrin Eller

doi:10.3390/jcm10040832

Abstract

Selectively targeting the E-type prostanoid receptor 4 (EP4) might be a new therapeutic option in the treatment of glomerulonephritis (GN), since the EP4 receptor is expressed on different immune cells, resident kidney cells, and endothelial cells, which are all involved in the pathogenesis of immune-complex GN. This study aimed to evaluate the therapeutic potential and to understand the mode of action of EP4 agonist in immune-complex GN using the murine model of nephrotoxic serum nephritis (NTS). In vivo, NTS mice were treated two times daily with two different doses of an EP4 agonist ONO AE1-329 or vehicle for 14 days total. The effect of PGE2 and EP4 agonism and antagonism was tested on murine distal convoluted tubular epithelial cells (DCT) in vitro. In vivo, the higher dose of the EP4 agonist led to an improved NTS phenotype, including a reduced tubular injury score and reduced neutrophil gelatinase-associated lipocalin (NGAL) and blood urea nitrogen (BUN) levels. EP4 agonist treatment caused decreased CD4+ T cell infiltration into the kidney and increased proliferative capacity of tubular cells. Injection of the EP4 agonist resulted in dose-dependent vasodilation and hypotensive episodes. The low-dose EP4 agonist treatment resulted in less pronounced episodes of hypotension. In vitro, EP4 agonism resulted in cAMP production and increased distal convoluted tubular (DCT) proliferation. Taken together, EP4 agonism improved the NTS phenotype by various mechanisms, including reduced blood pressure, decreased CD4+ T cell infiltration, and a direct effect on tubular cells leading to increased proliferation probably by increasing cAMP levels.

Highlights

The lipid molecule prostaglandin (PG)E2 mediates pro- and anti-inflammatory effects depending on its local concentration and on the cell type and receptors involved [1,2]
Whereas low doses of the E-type prostanoid receptor 4 (EP4) agonist histologically resembled vehicle-treated mice, high doses of the EP4 agonist resulted in an overall improved histological phenotype (Figure 1A)
This was reflected by decreased mean arterial pressure (MAP) (Figure 2) after the injection of the high and low doses of the EP4 agonist as evaluated by tail-cuff measurements

Summary

Introduction

The lipid molecule prostaglandin (PG)E2 mediates pro- and anti-inflammatory effects depending on its local concentration and on the cell type and receptors involved [1,2]. Due to its short half-life, PGE2 is supposed to act locally at the site of production. G2 (PGG2) and further reduced to prostaglandin H2 (PGH2) by the cyclooxygenases. The different PG subtypes originate from the intermediate PGH2. These subtypes include the prostanoids: Prostaglandin E2 (PGE2), prostacyclin (PGI2), prostaglandin F2α (PGF2α), prostaglandin D2 (PGD2), and thromboxane A2 (TXA2) [1,3,4]. The ubiquitously occurring PGE2 is linked to mediation of pain, fever, inflammation, the regulation of blood pressure, renal perfusion, angiogenesis, and tumor growth. Various functions of PGE2 are mediated by the four different G-coupled receptors, namely EP1–4

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