Low-dose darbepoetin alpha attenuates progression of a mouse model of aristolochic acid nephropathy through early tubular protection.
OBJECTIVE
Aristolochic acid (AA) nephropathy, first reported as Chinese herbs nephropathy, is a rapidly progressive tubulointerstitial nephropathy that results in severe anemia, interstitial fibrosis and end-stage renal disease. Tubulointerstitial injury was studied in a mouse model of AA nephropathy to determine whether low-dose darbepoetin alpha (DPO) treatment prevents acute tubular necrosis and interstitial fibrosis.


METHODS
AA was administered to C3H/He mice intraperitoneally and some mice were also treated with 0.1 microg/kg of DPO weekly starting on the day of AA administration or on day 28. At 28, 56 or 84 days, blood and urine samples were collected and mice were sacrificed for histological assessment of the kidneys.


RESULTS
AA-treated mice developed anemia, elevation of serum creatinine, severe tubular injury similar to acute tubular necrosis and progressive interstitial fibrosis. Although early treatment with low-dose DPO had minimal effects on the hematocrit, it significantly ameliorated acute tubular injury and interstitial inflammation through increasing the survival of tubular cells. As a result, it contributed to preservation of peritubular capillaries and reduction of interstitial fibrosis.


CONCLUSIONS
Low-dose DPO treatment conferred protection against acute tubular damage and attenuated interstitial fibrosis in a mouse model of AA nephropathy. Early administration of low-dose DPO may prevent the progression of acute tubular necrosis and the subsequent renal fibrosis in human AA nephropathy.
Hamano
Yuki
Y
Department of Nephrology, Chiba University Hospital, Chiba, Japan. hamano @ faculty.chiba-u.jp
Aoki
Takahiro
T
Shirai
Ryota
R
Hatano
Megumi
M
Kimura
Ryota
R
Ogawa
Makoto
M
Yokosuka
Osamu
O
Ueda
Shiro
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D034341:Aristolochic Acids; D049109:Cell Proliferation / Q000187:drug effects; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005355:Fibrosis / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H
D034341:Aristolochic Acids; D004921:Erythropoietin; D000068256:Darbepoetin alfa; C000228:aristolochic acid I