Partial depletion of macrophages by ED7 reduces renal injury in Adriamycin nephropathy.
BACKGROUND
Because macrophages are considered to be possible effectors of disease in Adriamycin (ADR) nephrosis, we hypothesized that depletion of macrophages might protect against the initiation of renal injury. In the present study, a monoclonal antibody (ED7) directed against CD11b/CD18 integrin, which is expressed by macrophages, was used to investigate the pathogenetic effects of macrophages in ADR nephropathy.


METHODS
Male Wistar rats were treated with ED7 antibody, starting 1 day prior to ADR (7.5 mg/kg) treatment, or 7 days post-ADR when overt proteinuria was established.


RESULTS
Circulating ED7-positive cells were reduced by approximately 30% in rats with ADR nephrosis by the ED7 antibody, while the number of macrophages in the renal cortex of ADR rats was reduced by nearly 50% with the ED7 treatment, whether administered before or after ADR. Creatinine clearance was significantly ameliorated by ED7 when commenced pre-ADR (P < 0.05), but not when commenced post-ADR (P = NS) in comparison to untreated ADR rats. However, proteinuria was not alleviated by either ED7 treatment. Morphometric analysis showed less glomerular sclerosis when ED7 was commenced pre-ADR compared with ADR alone (P < 0.01), but not when commenced post-ADR (P = NS). Tubular atrophy was reduced by ED7 when it was commenced pre-ADR (tubular cell height and tubular diameter: P < 0.01 and P < 0.001, respectively), as was interstitial expansion (P < 0.01) compared with ADR alone. Cortical macrophage infiltration was reduced by 50% compared with ADR alone by the ED7 commenced before or after ADR. The number of cortical CD4+ T cells fell with ED7 starting pre-ADR, but not with the ED7 treatment commencing after ADR.


CONCLUSIONS
Partial macrophage depletion starting before but not after ADR protected both renal function and structure in this model of chronic proteinuric renal disease.
Wang
Yiping
Y
Department of Renal Medicine, The University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales, Australia.
Mahajan
Deepika
D
Tay
Yuet-Ching
YC
Bao
Shisan
S
Spicer
Tim
T
Kairaitis
Lukas
L
Rangan
Gopala K
GK
Harris
David C H
DC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002908:Chronic Disease; D004317:Doxorubicin / Q000633:toxicity*; D047589:Leukocyte Reduction Procedures; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D004317:Doxorubicin