1. Cyclooxygenase-2, prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney.
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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., and Sharma, Mukut
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CYCLOOXYGENASE 2 ,DINOPROSTONE ,PROSTANOIDS ,SHEARING force ,CYTOSKELETON ,INDOMETHACIN - 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 (PGE
2 ) 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 Palb umin permeability (PP ) in vitro. FFSS caused an increase in PPalb alb 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 Palb umin 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 Palb uminuria 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. [ABSTRACT FROM AUTHOR]- Published
- 2014
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