Up-regulation of parathyroid hormone-related protein in folic acid-inducedacute renal failure

Background. Parathyroid hormone (PTH)-related protein (PTHrP) is present in many normal tissues, including the kidney. Current evidence supports that PTHrP is involved in renal pathophysiology, although its role on the mechan isms of renal damage and/or repair is unclear. Our present study examined t he changes in PTHrP and the PTH/PTHrP receptor (type 1) in folic acid-induc ed acute renal failure in rats. The possible role of PTHrP on the process o f renal regeneration following folic acid administration, and potential int eraction between angiotensin II (Ang II) and endothelin-1, and PTHrP, were examined in this animal model. Methods. PTHrP, PTH/PTHrP receptor, ACE, and preproendothelin-1 (preproET-1 ) mRNA levels in the rat kidney were analyzed by reverse transcription-poly merase chain reaction (RT-PCR) and/or RNase protection assay. Immunohistoch emistry also was performed for PTHrP, the PTH/PTHrP receptor, and Ang II in the renal tissue of folic acid-injected rats. The role of PTHrP on tubular cell proliferation following folic acid injury was investigated in vitro i n rat renal epithelial cells (NRK 52E). PTHrP secretion in the medium condi tioned by these cells was measured by an immunoradiometric assay specific f or the 1-36 sequence. Results. Using RT-PCR, PTHrP mRNA was rapidly (1 hour) and maximally increa sed (3-fold) in the rat kidney after folic acid, decreasing after six hours . At 72 hours, renal function was maximally decreased in these rats, associ ated with an increased PTHrP immunostaining in both renal tubules and glome ruli. In contrast, the PTH/PTHrP receptor mRNA (RNase protection assay) dec reased shortly after folic acid administration. Moreover, PTH/PTHrP recepto r immunostaining dramatically decreased in renal tubular cell membranes aft er folic acid. A single subcutaneous administration of PTHrP (1-36), 3 or 5 0 mug/kg body weight, shortly after folic acid injection increased the numb er of tubular cells staining for proliferating cell nuclear antigen by 30% (P < 0.05) or 50% (P < 0.01), respectively, in these rats at 24 hours, with out significant changes in either renal function or calcemia. On the other hand, this peptide failed to modify the increase (2-fold over control) in A CE mRNA, associated with a prominent Ang II staining into tubular cell nucl ei, in the kidney of folic acid-treated rats at this time period. The addit ion of 10 mmol/L folic acid to NRK 52E cells caused a twofold increase in P THrP mRNA at six hours, without significant changes in the PTH/PTHrP recept or mRNA. The presence of two anti-PTHrP antibodies, with or without folic a cid, in the cell-conditioned medium decreased (40%, P < 0.01) cell growth. Conclusions. Renal PTHrP was rapidly and transiently increased in rats with folic acid-induced acute renal failure, featuring as an early response gen e. In addition, changes in ACE and Ang II expression were also found in the se animals. PTHrP induces a mitogenic response in folic acid-damaged renal tubular cells both in vivo and in vitro. Our results support the notion tha t PTHrP up-regulation participates in the regenerative process in this mode l of acute renal failure and is a common event associated with the mechanis ms of renal injury and repair.