Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

Mutsaers, Henricus A M; Nørregaard, Rikke

doi:10.23876/j.krcp.21.222

Cited by 16 publications

(12 citation statements)

References 80 publications

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“…1C and D). These results support the notion that prostaglandin E 2 receptors are potential targets for the treatment of renal fibrosis, in line with previous findings [5,6,11]. As shown in Fig.…”

Section: Resultssupporting

confidence: 93%

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

et al. 2023

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Objective Renal fibrosis is one of the main pathophysiological processes underlying the progression of chronic kidney disease and kidney allograft failure. In the past decades, overwhelming efforts have been undertaken to find druggable targets for the treatment of renal fibrosis, mainly using cell- and animal models. However, the latter often do not adequately reflect human pathogenesis, obtained results differ per strain within a given species, and the models are associated with considerable discomfort for the animals. Therefore, the objective of this study is to implement the 3Rs in renal fibrosis research by establishing an animal-free drug screening platform for renal fibrosis based on human precision-cut kidney slices (PCKS) and by limiting the use of reagents that are associated with significant animal welfare concerns. Results Using Western blotting and gene expression arrays, we show that transforming growth factor-β (TGF-β) induced fibrosis in human PCKS. In addition, our results demonstrated that butaprost, SC-19220 and tamoxifen – all putative anti-fibrotic compounds – altered TGF-β-induced pro-fibrotic gene expression in human PCKS. Moreover, we observed that all compounds modulated fairly distinct sets of genes, however they all impacted TGF-β/SMAD signaling. In conclusion, this study revealed that it is feasible to use an animal-free approach to test drug efficacy and elucidate mechanisms of action.

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Section: Resultssupporting

confidence: 93%

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

et al. 2023

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“…To our knowledge, our work is the first to confirm that pharmacological inhibition of the EP 1 receptor using SC‐19220 prevents the progression of fibrosis in a human renal fibrosis model. We and others have previously confirmed that other EP receptors, including EP 2 and EP 4 play significant roles in preventing kidney fibrosis 15,27 . Recently, Jensen et al showed that activation of the EP 2 receptor with butaprost mitigates fibrogenesis in human PCKS, 14 indicating that targeting the EP 2 receptor also directly prevents renal fibrosis in human kidney slices.…”

Section: Discussionmentioning

confidence: 53%

“…We and others have previously confirmed that other EP receptors, including EP 2 and EP 4 play significant roles in preventing kidney fibrosis. 15 , 27 Recently, Jensen et al showed that activation of the EP 2 receptor with butaprost mitigates fibrogenesis in human PCKS, 14 indicating that targeting the EP 2 receptor also directly prevents renal fibrosis in human kidney slices.…”

Section: Discussionmentioning

confidence: 99%

EP₁ receptor antagonism mitigates early and late stage renal fibrosis

et al. 2022

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Aim Renal fibrosis is a major driver of chronic kidney disease, yet current treatment strategies are ineffective in attenuating fibrogenesis. The cyclooxygenase/prostaglandin system plays a key role in renal injury and holds great promise as a therapeutic target. Here, we used a translational approach to evaluate the role of the PGE2‐EP1 receptor in the pathogenesis of renal fibrosis in several models of kidney injury, including human (fibrotic) kidney slices. Methods The anti‐fibrotic efficacy of a selective EP1 receptor antagonist (SC‐19220) was studied in mice subjected to unilateral ureteral obstruction (UUO), healthy and fibrotic human precision‐cut kidney slices (PCKS), Madin‐Darby Canine Kidney (MDCK) cells and primary human renal fibroblasts (HRFs). Fibrosis was evaluated on gene and protein level using qPCR, western blot and immunostaining. Results EP1 receptor inhibition diminished fibrosis in UUO mice, illustrated by a decreased protein expression of fibronectin (FN) and α‐smooth muscle actin (αSMA) and a reduction in collagen deposition. Moreover, treatment of healthy human PCKS with SC‐19220 reduced TGF‐β‐induced fibrosis as shown by decreased expression of collagen 1A1, FN and αSMA as well as reduced collagen deposition. Similar observations were made using fibrotic human PCKS. In addition, SC‐19220 reduced TGF‐β‐induced FN expression in MDCK cells and HRFs. Conclusion This study highlights the EP1 receptor as a promising target for preventing both the onset and late stage of renal fibrosis. Moreover, we provide strong evidence that the effect of SC‐19220 may translate to clinical care since its effects were observed in UUO mice, cells and human kidney slices.

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“…It has been reported that the expression of EP4, not EP2, was significantly increased after renal IRI, which is consistent with our findings, suggesting that EP4 is directly involved in the process of AKI ( Pan et al, 2022b ). However, several studies reported that EP4 activation enhanced kidney damage ( Vukicevic et al, 2006 ; Mutsaers and Norregaard, 2022 ). To comprehensively determine the dynamic alterations of EP4 in the process of AKI to CKD, snRNA-seq and flow cytometry were employed in this study to determine the dynamics of EP4 in the kidney tissues from mice with IRI.…”

Section: Discussionmentioning

confidence: 99%

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

et al. 2022

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Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.

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Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

Cited by 16 publications

References 80 publications

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

EP₁ receptor antagonism mitigates early and late stage renal fibrosis

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

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Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

Cited by 16 publications

References 80 publications

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

An animal-free preclinical drug screening platform based on human precision-cut kidney slices

EP1 receptor antagonism mitigates early and late stage renal fibrosis

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

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EP₁ receptor antagonism mitigates early and late stage renal fibrosis