Prostanoid receptors in hyperfiltration‐mediated glomerular injury: Novel agonists and antagonists reveal opposing roles for EP2 and EP4 receptors. Issue 10 (20th September 2022)

• Record Type: Journal Article
• Authors: Srivastava, Tarak; Garola, Robert E.; Zhou, Jianping; Boinpelly, Varun C.; Priya, Lakshmi; Ali, Mohammed Farhan; Rezaiekhaligh, Mohammad H.; Heruth, Daniel P.; Novak, Jan; Alon, Uri S.; Joshi, Trupti; Jiang, Yuexu; McCarthy, Ellen T.; Savin, Virginia J.; Johnson, Mark L.; Sharma, Ram; Sharma, Mukut
• Is Part Of: FASEB journal. Volume 36:Issue 10(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-20
• Subjects: fluid‐flow shear stress -- glomerular filtration barrier -- glomerular hemodynamics -- hyperfiltration -- podocytes; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202200875R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Increased fluid‐flow shear stress (FFSS) contributes to hyperfiltration‐induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 (but not EP4 expression), COX2‐PGE2 ‐EP2 axis, and EP2‐linked Akt‐GSK3β‐β‐catenin signaling pathway in podocytes. To understand and use the disparities between PGE2 receptors, specific agonists, and antagonists of EP2 and EP4 were used to assess phosphorylation of Akt, GSK3β and β‐catenin in podocytes using Western blotting, glomerular filtration barrier function using in vitro albumin permeability (Palb ) assay, and mitigation of hyperfiltration‐induced injury in unilaterally nephrectomized (UNX) mice at 1 and 6 months. Results show an increase in Palb by PGE2, EP2 agonist (EP2 AGO ) and EP4 antagonist (EP4 ANT ), but not by EP2 antagonist (EP2 ANT ) or EP4 agonist (EP4 AGO ). Pretreatment with EP2 ANT blocked the effect of PGE2 or EP2 AGO on Palb . Modulation of EP2 and EP4 also induced opposite effects on phosphorylation of Akt and β‐Catenin. Individual agonists or antagonists of EP2 or EP4 did not induce significant improvement in albuminuria in UNX mice. However, treatment with a combination EP2 ANT + EP4 AGO for 1 or 6 months caused a robust decrease in albuminuria. EP2 ANT + EP4 AGO combination did not impact adaptive hypertrophy or increased serum creatinine. Observed differences between expression of EP2 and EP4 on the glomerular barrier highlight these receptors as potential targets for intervention. Safe and effective mitigating effect of EP2 ANT + EP4 AGO presents a novel opportunity to delay the progression of hyperfiltration‐associated CKD as seen in transplant donors.