TY - JOUR
T1 - EP1 receptor antagonism mitigates early and late stage renal fibrosis
AU - Kresse, Jean Claude
AU - Mutsaers, Henricus A.M.
AU - Jensen, Michael Schou
AU - Tingskov, Stine Julie
AU - Madsen, Mia Gebauer
AU - Nejsum, Lene N.
AU - Prætorius, Helle
AU - Nørregaard, Rikke
N1 - Funding Information:
The authors thank Gitte Skou and Gitte Kall for expect technical assistance. We also would like to thank the surgeons at the Department of Urology, Aarhus University Hospital for providing human tissue sampels. Moreover, the authors thank Prof. RA Bank, University of Groningen, the Netherlands for contributing the human renal fibroblasts. The work was kindly supported by the Danish Council for Independent Research, grant number 6110-00231B, Aarhus University Foundation, grant number AUFF-E-2015-FLS-8-69, Karen Elise Jensens Foundation, Hildur and Dagny Jacobsens Foundation, grant number 1295716-1 and Edith Waagens and Frode Waagens Foundation (received by RN) as well as Lundbeckfonden, grant number R231-2016-2344 (received by HAMM).
Funding Information:
The authors thank Gitte Skou and Gitte Kall for expect technical assistance. We also would like to thank the surgeons at the Department of Urology, Aarhus University Hospital for providing human tissue sampels. Moreover, the authors thank Prof. RA Bank, University of Groningen, the Netherlands for contributing the human renal fibroblasts. The work was kindly supported by the Danish Council for Independent Research, grant number 6110‐00231B, Aarhus University Foundation, grant number AUFF‐E‐2015‐FLS‐8‐69, Karen Elise Jensens Foundation, Hildur and Dagny Jacobsens Foundation, grant number 1295716‐1 and Edith Waagens and Frode Waagens Foundation (received by RN) as well as Lundbeckfonden, grant number R231‐2016‐2344 (received by HAMM).
Publisher Copyright:
© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
KW - chronic kidney disease
KW - human precision-cut kidney slices
KW - prostaglandin E EP receptor
KW - renal fibrosis
UR - http://www.scopus.com/inward/record.url?scp=85123898995&partnerID=8YFLogxK
U2 - 10.1111/apha.13780
DO - 10.1111/apha.13780
M3 - Article
C2 - 34989478
AN - SCOPUS:85123898995
SN - 1748-1708
VL - 234
JO - Acta physiologica
JF - Acta physiologica
IS - 3
M1 - e13780
ER -