Faculty Collaboration Database

Cyclooxygenase-2, prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney. Am J Physiol Renal Physiol 2014 Dec 15;307(12):F1323-33

Date

09/23/2014

Pubmed ID

25234310

DOI

10.1152/ajprenal.00335.2014

Scopus ID

2-s2.0-84918802845 (requires institutional sign-in at Scopus site)   27 Citations

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.

Author List

Srivastava T, Alon US, Cudmore PA, Tarakji B, Kats A, Garola RE, Duncan RS, McCarthy ET, Sharma R, Johnson ML, Bonewald LF, El-Meanawy A, Savin VJ, Sharma M

Author

Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Albuminuria
Animals
Cell Line
Cyclooxygenase 2
Cyclooxygenase Inhibitors
Dinoprostone
Disease Models, Animal
Kidney Glomerulus
Male
Mice
Mice, 129 Strain
Nephrectomy
Podocytes
RNA, Messenger
Receptors, Prostaglandin E, EP2 Subtype
Renal Circulation
Renal Insufficiency, Chronic
Signal Transduction
Stress, Mechanical
Time Factors
Up-Regulation