Blockade of prostaglandin E₂ receptor 4 ameliorates nephrotoxic serum nephritis

Abstract

Prostaglandin E2 (PGE2) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE2 [E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt−1·day−1] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand ( Cxcl) 1 and Cxcl-5 expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5 mRNA and Cxcl-5 protein when treated with PGE2 or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.

The Effect of Interleukin-4 and Dexamethasone on RNA-Seq-Based Transcriptomic Profiling of Human Podocytes: A Potential Role in Minimal Change Nephrotic Syndrome

“…Of the two positively expressed DEGs, PTGER4 (prostaglandin E receptor 4) encodes for prostaglandin (PG) E4, and PGE2 is known to induce cyclooxygenase (COX)-2 expression in podocytes via the PGE4 receptor [ 35 , 36 ]. Enhanced expression of E-prostanoid receptor 4 (EP4) in cultured podocytes was shown to negatively affect podocyte adaptation to mechanical stretch [ 37 ], while the inhibition of EP4 attenuated the development of nephropathy in rodent models [ 38 , 39 ]. Additionally, EP4 inhibition prevented the TGF-ß1-induced dedifferentiation of glomerular podocytes [ 39 ].…”

“…Enhanced expression of E-prostanoid receptor 4 (EP4) in cultured podocytes was shown to negatively affect podocyte adaptation to mechanical stretch [ 37 ], while the inhibition of EP4 attenuated the development of nephropathy in rodent models [ 38 , 39 ]. Additionally, EP4 inhibition prevented the TGF-ß1-induced dedifferentiation of glomerular podocytes [ 39 ]. In our study, the marked upregulation of PTGER4 expression suggests that IL-4 may have triggered the EP4-induced pathogenic process.…”

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

“…For the evaluation of crescents, a minimum of 50 glomerular cross-sections were evaluated. PAS-positive material within glomeruli was scored according to a semiquantitative scoring system as published recently [ 29 ].…”

“…There is evidence that targeting EP4 in this disease model influences disease outcome. Our group recently showed that the EP4 antagonism protects mice from NTS by downregulation of chemokine (C-X-C motif) ligand (CXCL)-5 in tubular cells, thereby inhibiting the recruitment of neutrophil granulocytes to the kidney [ 29 ]. Interestingly, positive effects of EP4 agonists on the kidney phenotype have been described in the past without providing clear evidence of the exact mechanism [ 30 ].…”

International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin E2Receptors (EP1–4) and Prostacyclin Receptor (IP): Specific Roles in Pathophysiologic Conditions

“…An EP4 receptor-derived peptide, which acts as a negative allosteric modulator, restored renal function in models of acute renal failure (Leduc et al, 2013), and EP4 antagonists prevented inflammation and renal impairment in a mouse model of acute glomerulonephritis (Aringer et al, 2018).…”