Article Text

Download PDFPDF
Renoprotection With Pituitary Adenylate Cyclase-Activating Polypeptide in Cyclosporine A-Induced Nephrotoxicity


Background Acute and long-term nephrotoxicity is the major dose-limiting factor for cyclosporine A (CsA). We evaluated the protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP)38 on CsA-induced nephrotoxicity in human renal proximal tubule epithelial (human kidney-2) cells and in intact mice.

Methods Confluent (human kidney-2 cells were exposed to CsA (25-50 μmol/L) in the presence or absence of PACAP38 or vasoactive intestinal peptide (10−10 to 10−6 M). For studies in vivo, male BALB/c mice (n = 5 in each group) were given a single intraperitoneal injection of CsA (5 mg/kg body weight). Treatment group received 20 μg of PACAP38 2 hours before exposure to CsA and additional doses daily for 10 days.

Results Cyclosporine A caused oxidative injury, marked morphological alterations, apoptosis, and increased expression of transforming growth factor (TGF)-β1 in cell cultures. Pituitary adenylate cyclase-activating polypeptide 38 at 10−8 mol/L restored cell confluency, reduced TGF-β1 secretion, and preserved cell integrity. In mice, CsA caused tubular injury characterized by loss of tubular epithelial cell brush border membranes, tubular collapse, cellular necrosis, interstitial fibrosis, increased production of TGF-β1, and elevated serum creatinine (3.39 ± 0.21 vs 0.13 ± 0.02 mg/dL in controls, P < 0.01). Treatment with PACAP38 reduced TGF-β1 and tumor necrosis factor-α production in kidney, prevented epithelial-mesenchymal transition of the renal cells, and reduced serum creatinine levels to 1.01 ± 0.18 mg/dL, P < 0.01 versus CsA group.

Conclusions Pituitary adenylate cyclase-activating polypeptide 38 ameliorated renal tubular injury, reduced oxidative injury, and inhibited the expression of TGF-β1 in CsA-exposed murine kidneys. Pituitary adenylate cyclase-activating polypeptide could be a novel renoprotective and antifibrotic agent for CsA nephrotoxicity.

Key Words
  • antifibrotic
  • interstitial fibrosis
  • neuropeptide
  • tumor growth factor-β1
  • apoptosis
  • calcineurin inhibitor

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.