title: Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity.
abstract: Parathyroid hormone-related protein (PTHrP) is shortly upregulated in acute renal injury, but its pathophysiologic role is unclear. Investigated was whether PTHrP might act as a profibrogenic factor in mice that do or do not overexpress PTHrP in the proximal tubule after folic acid (FA) nephrotoxicity, a model of acute renal damage followed by partial regeneration and patchy tubulointerstitial fibrosis. It was found that constitutive PTHrP overexpression in these animals conveyed a significant increase in tubulointerstitial fibrosis, associated with both fibroblast activation (as alpha-smooth muscle actin staining) and macrophage influx, compared with control littermates at 2 to 3 wk after FA damage. Cell proliferation and survival was higher (P<0.01) in the renal interstitium of PTHrP-overexpressing mice than in control littermates within this period after injury. Moreover, the former mice had a constitutive Bcl-XL protein overexpression. In vitro studies in renal tubulointerstitial and fibroblastic cells strongly suggest that PTHrP (1-36) (100 nM) reduced FA-induced apoptosis through a dual mechanism involving Bcl-XL upregulation and Akt and Bad phosphorylation. PTHrP (1-36) also stimulated monocyte chemoattractant protein-1 expression in tubuloepithelial cells, as well as type-1 procollagen gene expression and fibronectin (mRNA levels and protein secretion) in these cells and renal fibroblastic cells. Our findings indicate that this peptide, by interaction with the PTH1 receptor, can increase tubulointerstitial cell survival and seems to act as a proinflammatory and profibrogenic factor in the FA-damaged kidney.
authors: Laboratorio de Metabolismo Mineral y Oseo, Pathology Department, Fundación Jiménez and Universidad Autónoma de Madrid, Spain.
authors: Arantxa
authors: A
authors: Ortega
authors: David
authors: D
authors: Rámila
authors: Juan Antonio
authors: JA
authors: Ardura
authors: Vanesa
authors: V
authors: Esteban
authors: Marta
authors: M
authors: Ruiz-Ortega
authors: Antonio
authors: A
authors: Barat
authors: Rosa
authors: R
authors: Gazapo
authors: Ricardo J
authors: RJ
authors: Bosch
authors: Pedro
authors: P
authors: Esbrit