Mitigation of radiation nephropathy after internal alpha-particle irradiation of kidneys.
OBJECTIVE
Internal irradiation of kidneys as a consequence of radioimmunotherapy, radiation accidents, or nuclear terrorism can result in radiation nephropathy. We attempted to modify pharmacologically, the functional and morphologic changes in mouse kidneys after injection with the actinium ((225)Ac) nanogenerator, an in vivo generator of alpha- and beta-particle emitting elements.


METHODS
The animals were injected with 0.35 muCi of the (225)Ac nanogenerator, which delivers a dose of 27.6 Gy to the kidneys. Then, they were randomized to receive captopril (angiotensin-converting enzyme inhibitor), L-158,809 (angiotensin II receptor-1 blocker), spironolactone (aldosterone receptor antagonist), or a placebo.


RESULTS
Forty weeks after the (225)Ac injection, the placebo-control mice showed a significant increase in blood urea nitrogen (BUN) (87.6 +/- 6.9 mg/dL), dilated Bowman spaces, and tubulolysis with basement membrane thickening. Captopril treatment accentuated the functional (BUN 119.0 +/- 4.0 mg/dL; p <0.01 vs. placebo controls) and histopathologic damage. In contrast, L-158,809 offered moderate protection (BUN 66.6 +/- 3.9 mg/dL; p = 0.02 vs. placebo controls). Spironolactone treatment, however, significantly prevented the development of histopathologic and functional changes (BUN 31.2 +/- 2.5 mg/dL; p <0.001 vs. placebo controls).


CONCLUSIONS
Low-dose spironolactone and, to a lesser extent, angiotensin receptor-1 blockade can offer renal protection in a mouse model of internal alpha-particle irradiation.
Jaggi
Jaspreet Singh
JS
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Seshan
Surya V
SV
McDevitt
Michael R
MR
Sgouros
George
G
Hyjek
Elizabeth
E
Scheinberg
David A
DA
D000186:Actinium / Q000633:toxicity*; D000512:Alpha Particles; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity; D000818:Animals; D001806:Blood Urea Nitrogen; D002216:Captopril / Q000633:toxicity; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000139:chemically induced / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000627:therapeutic use* / Q000633:toxicity; D011897:Random Allocation; D013148:Spironolactone / Q000627:therapeutic use; D013777:Tetrazoles / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D000451:Mineralocorticoid Receptor Antagonists; D011837:Radiation-Protective Agents; D013777:Tetrazoles; D000804:Angiotensin II; D013148:Spironolactone; C070967:L 158809; D002216:Captopril; D000186:Actinium