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Renoprotection With Pituitary Adenylate Cyclase-Activating Polypeptide in Cyclosporine A-Induced Nephrotoxicity
  1. Altaf-M Khan, PhD*,
  2. Min Li, MD, PhD*,
  3. Elizabeth Brant, MD*,
  4. Jerome L. Maderdrut, PhD,
  5. Dewan S.A. Majid, PhD,
  6. Eric E. Simon, MD,
  7. Vecihi Batuman, MD
  1. From the *Section of Nephrology and Hypertension, †Peptide Research Laboratory, Department of Medicine, ‡Department of Physiology, Tulane University School of Medicine; and §Southeast Louisiana Veterans Health Care System, New Orleans, LA.
  1. Received July 27, 2010, and in revised form January 29, 2011.
  2. Accepted for publication January 30, 2011.
  3. Reprints: Vecihi Batuman, MD, FACP, FASN, Nephrology Section-SL45, Tulane University Medical School, 1430 Tulane Ave, New Orleans, LA 70112-2632. E-mail: vbatuma{at}
  4. This work was supported in part by research grants from the Research Commercialization and Educational Enhancement Program of the Louisiana Board of Regents (ML, JLM, and VB), the Rudolph Matas Memorial Fund (VB and ML), DCI Research Endowment Fund (VB), the Louisiana Cancer Research Consortium (JLM), and the Arimura Foundation (ML).


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

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