Accelerated recovery from irradiation injury by angiotensin peptides.
OBJECTIVE
Angiotensin peptides have been shown to affect the proliferation and chemotaxis of multiple cell types. More recent studies in this laboratory have shown that angiotensin II (AII) can increase colony formation and proliferation by hematopoietic progenitors and mesenchymal cells in vitro. As white blood cell (WBC) recovery after bone marrow injury requires progenitor proliferation, the effect of AII and angiotensin (1-7) [A(1-7)], a non-hypertensive fragment of AII, on recovery from total body irradiation was evaluated in C57Bl/6 mice.


METHODS
The effect of angiotensin peptides on hematopoietic recovery and the number of progenitors in the bone marrow of irradiated C57Bl/6 mice was evaluated.


RESULTS
Treatment of animals with angiotensin peptides accelerated hematopoietic recovery and increased the number of hematopoietic progenitors in bone marrow and in the blood. The increase in WBC concentration continued for a longer time after cessation of AII therapy than after treatment with filgrastim. Specifically, the number of WBCs continued to increase 21 days after irradiation with 7 days of angiotensin peptide administration. In contrast, the number of WBCs increased through day 13 with 7 days of filgrastim administration. On day 35 after irradiation (28 days after the last treatment), AII was shown to have increased the number of CFU-GM in the bone marrow of irradiated mice, whereas filgrastim administration had not. Angiotensin peptides also reduced the drop in platelet concentration after irradiation and increased the number of megakaryocyte precursors and megakaryocytes in the bone marrow. Receptor blocking studies indicated that losartan, an antagonist of the angiotensin type 1 receptor, blocked recovery of WBC levels in response to treatment with AII. In contrast, the increase in WBC levels in response to treatment with A(1-7), a ligand for other angiotensin receptors, was not affected by losartan.


CONCLUSIONS
These findings suggest that these peptides utilize distinct receptors in the stimulation of hematopoietic recovery. In summary, systemic administration of angiotensin peptides led to an acceleration in hematopoietic recovery after irradiation. These peptides act to stimulate the formation of bone marrow progenitors, thereby facilitating recovery after myelosuppressive irradiation.
Rodgers
Kathleen E
KE
University of Southern California, Keck School of Medicine, 1321 N. Mission Road, Los Angeles, CA 90033, USA. krodgers@hsc.usc.edu
Xiong
Shiquin
S
diZerega
Gere S
GS
D000803:Angiotensin I / Q000627:therapeutic use; D000804:Angiotensin II / Q000627:therapeutic use*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000528:radiation effects; D003114:Colony-Forming Units Assay; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D007958:Leukocyte Count; D018655:Lymphocyte Count; D008533:Megakaryocytes / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use*; D010976:Platelet Count; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D011994:Recombinant Proteins; D013234:Stem Cells / Q000187:drug effects / Q000528:radiation effects
D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D000804:Angiotensin II; D016179:Granulocyte Colony-Stimulating Factor; D000803:Angiotensin I; C118790:angiotensin I (1-7); D000069585:Filgrastim