title: Cyclooxygenase-2, prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney.
abstract: Hyperfiltration subjects podocytes to increased tensile stress and fluid flow shear stress (FFSS). We showed a 1.5- to 2.0-fold increase in FFSS in uninephrectomized animals and altered podocyte actin cytoskeleton and increased synthesis of prostaglandin E2 (PGE2) following in vitro application of FFSS. We hypothesized that increased FFSS mediates cellular changes through specific receptors of PGE2. Presently, we studied the effect of FFSS on cultured podocytes and decapsulated isolated glomeruli in vitro, and on solitary kidney in uninephrectomized sv129 mice. In cultured podocytes, FFSS resulted in increased gene and protein expression of cyclooxygenase (COX)-2 but not COX-1, prostanoid receptor EP2 but not EP4, and increased synthesis and secretion of PGE2, which were effectively blocked by indomethacin. Next, we developed a special flow chamber for applying FFSS to isolated glomeruli to determine its effect on an intact glomerular filtration barrier by measuring change in albumin permeability (Palb) in vitro. FFSS caused an increase in Palb that was blocked by indomethacin (P < 0.001). Finally, we show that unilateral nephrectomy in sv129 mice resulted in glomerular hypertrophy (P = 0.006), increased glomerular expression of COX-2 (P < 0.001) and EP2 (P = 0.039), and increased urinary albumin excretion (P = 0.001). Activation of the COX-2-PGE2-EP2 axis appears to be a specific response to FFSS in podocytes and provides a mechanistic basis for alteration in podocyte structure and the glomerular filtration barrier, leading to albuminuria in hyperfiltration-mediated kidney injury. The COX-2-PGE2-EP2 axis is a potential target for developing specific interventions to ameliorate the effects of hyperfiltration-mediated kidney injury in the progression of chronic kidney disease.
authors.affiliation: Section of Nephrology, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri; Renal Research Laboratory, Research and Development, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri; tsrivastava@cmh.edu.
authors.forename: Tarak
authors.initials: T
authors.lastname: Srivastava
authors.affiliation: Section of Nephrology, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: Uri S
authors.initials: US
authors.lastname: Alon
authors.affiliation: Section of Nephrology, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cudmore
authors.affiliation: Section of Nephrology, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: Belal
authors.initials: B
authors.lastname: Tarakji
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: Alexander
authors.initials: A
authors.lastname: Kats
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: Robert E
authors.initials: RE
authors.lastname: Garola
authors.affiliation: Section of Infectious Diseases, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri;
authors.forename: R Scott
authors.initials: RS
authors.lastname: Duncan
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas;
authors.forename: Ellen T
authors.initials: ET
authors.lastname: McCarthy
authors.affiliation: Renal Research Laboratory, Research and Development, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri;
authors.forename: Ram
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Oral Biology, University of Missouri-Kansas City School of Dentistry, Kansas City, Missouri; and.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Department of Oral Biology, University of Missouri-Kansas City School of Dentistry, Kansas City, Missouri; and.
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.affiliation: Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Ashraf
authors.initials: A
authors.lastname: El-Meanawy
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Renal Research Laboratory, Research and Development, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri;
authors.forename: Virginia J
authors.initials: VJ
authors.lastname: Savin
authors.affiliation: Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas; Renal Research Laboratory, Research and Development, Kansas City Veterans Affairs Medical Center, Kansas City, Missouri;
authors.forename: Mukut
authors.initials: M
authors.lastname: Sharma
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000503:physiopathology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D007678:Kidney Glomerulus / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D009392:Nephrectomy; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D012079:Renal Circulation / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D013314:Stress, Mechanical; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D016861:Cyclooxygenase Inhibitors; C545645:Ptger2 protein, mouse; C545646:Ptger2 protein, rat; D012333:RNA, Messenger; D058307:Receptors, Prostaglandin E, EP2 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D015232:Dinoprostone
keywords: fluid flow shear stress; glomerular filtration barrier; glomerular hemodynamics; hyperfiltration; podocytes