La proteína relacionada con la parathormona como una nueva citoquina proinflamatoria renal-estudios en un modelo experimental de nefropatía obstructiva

Abstract

Parathyroid hormone-related protein (PTHrP) has recently shown to promote fibrosis in a model of nephrotoxic acute renal injury by folic acid. Inflammation is a major event associated with fibrogenesis in the damaged kidney. In the present Doctoral Thesis, we assessed whether PTHrP might act as a renal proinflammatory factor after unilateral ureteral obstruction in mice, a well characterized model of inflammation. To this aim, we used mice overexpressing PTHrP specifically in the proximal tubule, as well as normal mice with pharmacological modulation of renal PTHrP expression. Furthermore, in vitro studies were performed to elucidate the mechanisms implicated in the proinflammatory actions of PTHrP in mouse tubuloepithelial cells and macrophages. Our findings demonstrate the critical role of PTHrP on the inflammatory process following kidney obstruction in mice. In vitro data indicate that this protein increases the expression of several pro-inflammatory factors in tubuloepithelial cells, and promotes monocyte/macrophage migration. Moreover, sequential activation of extracellular signal-related kinase (ERK) and nuclear factor(NF)-κB seems to be an important pathway whereby PTHrP may trigger renal inflammation. PTHrP is thus emerging as a new inflammation marker and a putative therapeutic target in the obstructed kidney.