Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids

Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces, namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a significant role of COX-2 generated PGE₂ and its receptors in response to tensile stress and FFSS. Preliminary observations show increased urinary PGE₂ in children born with a solitary kidney. FFSS-induced COX2-PGE₂-EP₂ signaling provides an opportunity to identify targets and, for developing novel agents to complement currently available treatment.