Cyclooxygenase-2, Prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney

Tarak Srivastava, Uri S. Alon, Patricia A. Cudmore, Belal Tarakji, Alexander Kats, Robert E. Garola, R. Scott Duncan, Ellen T. McCarthy, Ram Sharma, Mark L. Johnson, Lynda F. Bonewald, Ashraf El-Meanawy, Virginia J. Savin, Mukut Sharma

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)F1323-F1333
JournalAmerican Journal of Physiology - Renal Physiology
Volume307
Issue number12
DOIs
StatePublished - Dec 15 2014

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Receptors, Prostaglandin E, EP2 Subtype
Podocytes
Cyclooxygenase 2
Dinoprostone
Kidney
Wounds and Injuries
Glomerular Filtration Barrier
Indomethacin
Albumins
Cyclooxygenase 1
Albuminuria
Nephrectomy
Actin Cytoskeleton
Chronic Renal Insufficiency
Hypertrophy
Permeability
Gene Expression

Keywords

  • Fluid flow shear stress
  • Glomerular filtration barrier
  • Glomerular hemodynamics
  • Hyperfiltration
  • Podocytes

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Cyclooxygenase-2, Prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney. / Srivastava, Tarak; Alon, Uri S.; Cudmore, Patricia A.; Tarakji, Belal; Kats, Alexander; Garola, Robert E.; Scott Duncan, R.; McCarthy, Ellen T.; Sharma, Ram; Johnson, Mark L.; Bonewald, Lynda F.; El-Meanawy, Ashraf; Savin, Virginia J.; Sharma, Mukut.

In: American Journal of Physiology - Renal Physiology, Vol. 307, No. 12, 15.12.2014, p. F1323-F1333.

Research output: Contribution to journalArticle

Srivastava, T, Alon, US, Cudmore, PA, Tarakji, B, Kats, A, Garola, RE, Scott Duncan, R, McCarthy, ET, Sharma, R, Johnson, ML, Bonewald, LF, El-Meanawy, A, Savin, VJ & Sharma, M 2014, 'Cyclooxygenase-2, Prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney', American Journal of Physiology - Renal Physiology, vol. 307, no. 12, pp. F1323-F1333. https://doi.org/10.1152/ajprenal.00335.2014
Srivastava, Tarak ; Alon, Uri S. ; Cudmore, Patricia A. ; Tarakji, Belal ; Kats, Alexander ; Garola, Robert E. ; Scott Duncan, R. ; McCarthy, Ellen T. ; Sharma, Ram ; Johnson, Mark L. ; Bonewald, Lynda F. ; El-Meanawy, Ashraf ; Savin, Virginia J. ; Sharma, Mukut. / Cyclooxygenase-2, Prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney. In: American Journal of Physiology - Renal Physiology. 2014 ; Vol. 307, No. 12. pp. F1323-F1333.
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AU - Tarakji, Belal

AU - Kats, Alexander

AU - Garola, Robert E.

AU - Scott Duncan, R.

AU - McCarthy, Ellen T.

AU - Sharma, Ram

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