Adrenomedullin increases renal nitric oxide production and ameliorates renal injury in mice with unilateral ureteral obstruction.

Abstract

PURPOSE:

We evaluated the effects of adrenomedullin (Peptide Institute, Minoh-shi, Osaka, Japan) on mediators, including nitric oxide and transforming growth factor-beta, and parameters of renal injury in a murine unilateral ureteral obstruction model.

MATERIALS AND METHODS:

Three study groups of control, adrenomedullin treated and adrenomedullin plus L-NAME treated BALB/C mice, respectively, underwent left unilateral ureteral obstruction. A 24-hour urine sample was collected to measure urinary NO(2)/NO(3) 1 day before unilateral ureteral obstruction and kidneys were harvested on postoperative day 14. Tubulointerstitial damage markers were evaluated by immunohistochemistry. Tissue transforming growth factor-beta was determined by enzyme-linked immunosorbent assay. Endothelial and inducible nitric oxide synthase immunolocalization was also determined.

RESULTS:

Urinary NO(2)/NO(3) was significantly higher in the adrenomedullin group than in controls, confirming increased renal nitric oxide production. Immunohistochemistry showed increased endothelial nitric oxide synthase in vascular endothelial cells in the adrenomedullin group but tissue transforming growth factor-beta did not significantly differ in controls vs the adrenomedullin group. Interstitial collagen deposition and fibroblasts in the obstructed kidney were significantly decreased in the adrenomedullin group. The number of leukocytes and apoptotic cells in the obstructed kidney were significantly decreased by adrenomedullin. Renal injury amelioration resulting from adrenomedullin was blunted by the nitric oxide synthase inhibitor L-NAME.

CONCLUSIONS:

Adrenomedullin increased renal nitric oxide, and suppressed tubular apoptosis, interstitial fibrosis and inflammatory cell infiltration in mice with unilateral ureteral obstruction. The renoprotective peptide adrenomedullin may be useful for that condition.

• Authors: Keiichi Ito, Hidehiko Yoshii, Takako Asano, Kaori Seta, Yasunori Mizuguchi, Masanori Yamanaka, Shigeki Tokonabe, Masamichi Hayakawa, Tomohiko Asano
• Journal: The Journal of urology (J Urol) Vol. 183 Issue 4 Pg. 1630-5 (Apr 2010) ISSN: 1527-3792 [Electronic] United States
• PMID: 20172553 (Publication Type: Journal Article)
• Copyright: Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Transforming Growth Factor alpha
• Adrenomedullin
• Nitric Oxide

Topics

• Adrenomedullin (pharmacology, therapeutic use)
• Animals
• Mice
• Mice, Inbred BALB C
• Nitric Oxide (biosynthesis)
• Renal Insufficiency (drug therapy, etiology, metabolism)
• Transforming Growth Factor alpha (biosynthesis)
• Ureteral Obstruction (complications)