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 ␣-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-X L 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-X L 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.

Parathyroid Hormone–Related Protein Promotes Epithelial–Mesenchymal Transition

“…Snail also downregulates other epithelial markers but upregulates some mesenchymal markers (namely fibronectin and vitronectin) during EMT. 31,32 These findings further support and extend recent data, 22,24 indicating that PTHrP(1-36) promotes EMT in MCT cells.…”

“…Renal tubuloepithelial MCT cells and the human proximal tubule cell line HK-2, which respond to PTHrP(1-36), [22][23][24]50 were grown in RPMI 1640 with 10% FBS, supplemented with 1% insulin-transferrin-sodium selenite media (Sigma-Aldrich, St. Louis, MO) and hydrocortisone (36 ng/ml) (HK-2 cells), and antibiotics in 5% CO 2 at 37°C. Subconfluent …”

“…21 Recent studies in mice indicate that PTHrP can act as a proinflammatory and profibrogenic factor in the acutely damaged kidney after folic acid injection or unilateral ureteral obstruction. [22][23][24] Moreover, one of these studies strongly suggests that the profibrogenic action of PTHrP might be accounted for in part by promoting EMT through interaction with vascular endothelial growth factor (VEGF). 24 Interestingly in this scenario, it has previously been suggested that TGF-␤ might act as a modulator of at least some PTHrP actions through the PTH receptor 1 (PTHR1), common to PTH and PTHrP, in its target cells, such as tubuloepithelial cells and osteoblasts.…”

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

“…PI-3K activation by PTHrP may also occur independently of the α6β4 integrin. Thus, PTHrP may activate PI-3K via an autocrine/paracrine mechanism of action involving the PTH/PTHrP receptor, as has been reported in a mesenchymal cell line [71], and in renal tubulointerstitial and fibroblastic cells [72]. In this study, p-Akt levels were measured in cells plated on poly-D-lysine.…”

Mechanisms of Renal Apoptosis in Health and Disease

“…BAD dephosphorylation is observed in tubular cells exposed to proapoptotic stimuli. 22,23 In addition, phosphorylation by AKT limits the nuclear translocation of the Forkhead family of proapoptotic factors and promotes antiapoptotic NF-B and Mdm2, an antagonist of p53. 27 These or similar mechanisms may account for the development of a general intracellular milieu favoring survival in tubular cells exposed to survival factors.…”