Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice

Nasrallah, Rania; Zimpelmann, Joseph; Robertson, Susan J.; Ghossein, Jamie; Thibodeau, Jean-François; Kennedy, C. R.; Gutsol, Alex; Xiao, Fengxia; Burger, Dylan; Burns, Kevin D.; Hébert, Richard

doi:10.1038/s41374-019-0317-7

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…Several in vitro studies have demonstrated that EP 1 receptor activation can cause detrimental responses in different renal cell types, including mesangial cells, proximal tubule cells and podocytes. 16 , 28 , 29 In addition, in vivo studies have shown that a lack of the EP 1 receptor or EP 1 antagonism protects against hyperfiltration, albuminuria, and reduces injury/fibrotic markers in spontaneously hypertensive rats 17 , 30 and in diabetic mice models. 16 Conjointly, these data suggest that the EP 1 receptor mediates many pathologic effects in different kidney diseases, highlighting the importance of this receptor in renal diseases.…”

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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Section: Discussionmentioning

confidence: 99%

EP₁ receptor antagonism mitigates early and late stage renal fibrosis

et al. 2022

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“…In human studies, lesional variables are semi-quantified with distribution and/or severity descriptors because it is more practical for scoring small needle biopsies. Since whole kidneys are available in animals, each lesional variable was quantified with image analysis used in our previous studies [ 17 , 64 , 72 ]. Five lesional descriptors were quantified: mesangial expansion, mesangial cellularity, hyalinosis, FSGS, and GGS.…”

Section: Methodsmentioning

confidence: 99%

Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy

et al. 2022

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Current research on hypertension utilizes more than fifty animal models that rely mainly on stable increases in systolic blood pressure. In experimental hypertension, grading or scoring of glomerulopathy in the majority of studies is based on a wide range of opinion-based histological changes that do not necessarily comply with lesional descriptors for glomerular injury that are well-established in clinical pathology. Here, we provide a critical appraisal of experimental hypertensive glomerulopathy with the same approach used to assess hypertensive glomerulopathy in humans. Four hypertensive models with varying pathogenesis were analyzed–chronic angiotensin II infused mice, mice expressing active human renin in the liver (TTRhRen), spontaneously hypertensive rats (SHR), and Goldblatt two-kidney one-clip rats (2K1C). Analysis of glomerulopathy utilized the same criteria applied in humans–hyalinosis, focal segmental glomerulosclerosis (FSGS), ischemic, hypertrophic and solidified glomeruli, or global glomerulosclerosis (GGS). Data from animal models were compared to human reference values. Kidneys in TTRhRen mice, SHR and the nonclipped kidneys in 2K1C rats had no sign of hyalinosis, FSGS or GGS. Glomerulopathy in these groups was limited to variations in mesangial and capillary compartment volumes, with mild increases in collagen deposition. Histopathology in angiotensin II infused mice corresponded to mesangioproliferative glomerulonephritis, but not hypertensive glomerulosclerosis. The number of nephrons was significantly reduced in TTRhRen mice and SHR, but did not correlate with severity of glomerulopathy. The most substantial human-like glomerulosclerotic lesions, including FSGS, ischemic obsolescent glomeruli and GGS, were found in the clipped kidneys of 2K1C rats. The comparison of affected kidneys to healthy control in animals produces lesion values that are numerically impressive but correspond to mild damage if compared to humans. Animal studies should be standardized by employing the criteria and classifications established in human pathology to make experimental and human data fully comparable for comprehensive analysis and model improvements.

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“…Suganami et al [ 62 ] demonstrated, in stroke-prone spontaneously hypertensive rats, that treatment with ONO-8713 for 5 weeks improved renal function and attenuated the development of interstitial fibrosis. Conversely, in mice with long-standing hypertension, it was demonstrated that absence of the EP1 receptor was associated with a reduction in glomerular filtration as well as ultrastructural injury to podocytes and glomerular endothelium [ 63 ]. Interestingly, in both studies the impact of EP1 receptor modulation was observed despite persistent hypertension.…”

Section: The Role Of Prostaglandin E2 Ep Receptors In Development And...mentioning

confidence: 99%

Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

Mutsaers

Nørregaard

2022

Kidney Res Clin Pract

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Prostaglandin E2 (PGE2), a lipid mediator produced by the cyclooxygenase enzyme system, is the main prostaglandin in the kidney. PGE2 is involved in various physiological and pathophysiological processes in the kidney, including renal hemodynamics, water and salt balance, and renal fibrosis—a key pathological feature of progressive kidney diseases. PGE2 functions by binding to four G-protein-coupled EP receptors (EP1 to EP4), which stimulate different intracellular signaling pathways. The intrarenal distribution of the four EP receptors as well as the different downstream signaling pathways associated with each receptor give rise to the distinct functional consequence of activating each receptor subtype. This review summarizes the current data on the renal expression of the four EP receptors and delineates the role of each receptor in renal fibrosis.

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Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice

Cited by 11 publications

References 35 publications

EP₁ receptor antagonism mitigates early and late stage renal fibrosis

EP₁ receptor antagonism mitigates early and late stage renal fibrosis

Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy

Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

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Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice

Cited by 11 publications

References 35 publications

EP1 receptor antagonism mitigates early and late stage renal fibrosis

EP1 receptor antagonism mitigates early and late stage renal fibrosis

Comparative analysis of hypertensive nephrosclerosis in animal models of hypertension and its relevance to human pathology. Glomerulopathy

Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

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EP₁ receptor antagonism mitigates early and late stage renal fibrosis

EP₁ receptor antagonism mitigates early and late stage renal fibrosis