Role of parathyroid hormone-related protein in tubulointerstitial apoptosis and fibrosis after folic acid-induced nephrotoxicity.

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.

Role of the renin-angiotensin system on the parathyroid hormone-related protein overexpression induced by nephrotoxic acute renal failure in the rat.

Parathyroid hormone-related protein (PTHrP), a mitogenic factor for renal cells, is overexpressed in acute renal failure (ARF). Recent data support an association between PTHrP and the renin-angiotensin system in the damaged kidney. The effects of angiotensin II (Ang II) inhibitors (quinapril, enalapril, and/or losartan) on PTHrP and the PTH1 receptor (PTH1R) expression in rats with either folic acid (FA)- or gentamicin-induced ARF were analyzed. The decreased renal function and the PTHrP upregulation and PTH1R downregulation induced by the nephrotoxins were inhibited by the Ang II blockers. In tubuloepithelial cells NRK-52E, the rapid (10 min) increase in PTHrP mRNA by FA, associated with a perinuclear relocalization of Ang II/AT1 receptor, was inhibited by losartan but not candesartan, which traps Ang II receptors at the cell surface. Maximal PTHrP protein overexpression by FA (at 24 to 72 h)-or by exogenous Ang II-was abolished by both Ang II antagonists. PTHrP upregulation by FA was preceded by increased extracellular signal-regulated kinase (ERK) phosphorylation and inhibited by the ERK inhibitor PD098059. FA also activated cAMP response element-binding (CREB) protein, and this was prevented by losartan in these cells. Moreover, PTHrP mRNA overexpression by either FA or Ang II occurred in NRK 52E that were transfected with a CREB construct but not the dominant-negative CREB133 construct. These findings demonstrate that the decreased renal function and PTHrP overexpression in nephrotoxin-damaged kidney depends on renin-angiotensin system. In this setting, intracellular Ang II/AT1 receptor recycling seems to be related to PTHrP induction through ERK and CREB activation in tubuloepithelial cells.