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


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.
Ito
Keiichi
K
Department of Urology, National Defense Medical College, Tokorozawa, Saitama, Japan.
Yoshii
Hidehiko
H
Asano
Takako
T
Seta
Kaori
K
Mizuguchi
Yasunori
Y
Yamanaka
Masanori
M
Tokonabe
Shigeki
S
Hayakawa
Masamichi
M
Asano
Tomohiko
T
D053607:Adrenomedullin / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis*; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis; D014517:Ureteral Obstruction / Q000150:complications*
D016211:Transforming Growth Factor alpha; D053607:Adrenomedullin; D009569:Nitric Oxide