Attenuation of renal ischemia and reperfusion injury by human adrenomedullin and its binding protein.
BACKGROUND
Acute renal failure secondary to ischemia and reperfusion (I/R) injury poses a significant burden on both surgeons and patients. It carries a high morbidity and mortality rate and no specific treatment currently exists. Major causes of renal I/R injury include trauma, sepsis, hypoperfusion, and various surgical procedures. We have demonstrated that adrenomedullin (AM), a novel vasoactive peptide, combined with AM binding protein-1 (AMBP-1), which augments the activity of AM, is beneficial in various disease conditions. However, it remains unknown whether human AM/AMBP-1 provides any beneficial effects in renal I/R injury. The objective of our study therefore was to determine whether administration of human AM/AMBP-1 can prevent and/or minimize damage in a rat model of renal I/R injury.


METHODS
Male adult rats were subjected to renal I/R injury by bilateral renal pedicle clamping with microvascular clips for 60 min followed by reperfusion. Human AM (12 microg/kg BW) and human AMBP-1 (40 microg/kg BW) or vehicle (52 microg/kg BW human albumin) were given intravenously over 30 min immediately following the clip removal (i.e., reperfusion). Rats were allowed to recover for 24 h post-treatment, and blood and renal tissue samples were collected. Plasma levels of AM were measured using a radioimmunoassay specific for rat AM. Plasma AMBP-1 was measured by Western analysis. Renal water content and serum levels of systemic markers of tissue injury were measured. Serum and renal TNF-alpha levels were also assessed.


RESULTS
At 24 h after renal I/R injury, plasma levels of AM were significantly increased while plasma AMBP-1 was markedly decreased. Renal water content and systemic markers of tissue injury (e.g., creatinine, BUN, AST, and ALT) were significantly increased following renal I/R injury. Serum and renal TNF-alpha levels were also increased post injury. Administration of human AM/AMBP-1 decreased renal water content, and plasma levels of creatinine, BUN, AST, and ALT. Serum and renal TNF-alpha levels were also significantly decreased after AM/AMBP-1 treatment.


CONCLUSIONS
Treatment with human AM/AMBP-1 in renal I/R injury significantly attenuated organ injury and the inflammatory response. Thus, human AM combined with human AMBP-1 may be developed as a novel treatment for patients with acute renal I/R injury.
Shah
Kavin G
KG
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York 11030, USA.
Rajan
Derry
D
Jacob
Asha
A
Wu
Rongqian
R
Krishnasastry
Kambhampaty
K
Nicastro
Jeffrey
J
Molmenti
Ernesto P
EP
Coppa
Gene F
GF
Wang
Ping
P
D053607:Adrenomedullin / Q000097:blood / Q000627:therapeutic use*; D000510:Alpha-Globulins; D000818:Animals; D017242:Complement Factor H / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000097:blood / Q000517:prevention & control*; D008297:Male; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000097:blood / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014665:Vasodilator Agents / Q000627:therapeutic use*; D014867:Water / Q000378:metabolism
D053607:Adrenomedullin; D000510:Alpha-Globulins; D017242:Complement Factor H; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D014867:Water; C016001:alpha-1-microglobulin; C493495:CFH protein, human