The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy.
BACKGROUND
Macrophages play diverse roles in tissue injury. We evaluated their role in cyclosporine (CsA)-induced renal injury by depletion with liposomal clodronate (CL).


METHODS
Male Sprague Dawley rats were treated with CsA with or without CL treatment for 28 days. We assessed responses from the pathology and by measuring renal functions and levels of a proinflammatory cytokine (osteopontin), a profibrotic cytokine (betaig-h3), innate immune response markers (toll-like receptor 2 and MHC class II molecules), apoptotic cell death (deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling staining and caspase-3 expression) and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG).


RESULTS
Macrophage depletion with CL improved not only renal function but also histopathology compared with the CsA-treated rats. Osteopontin and betaig-h3 levels increased significantly in CsA-treated rat kidneys, but CL treatment decreased both markers. Enhanced innate immune response and apoptotic cell death in CsA-treated rat kidney were decreased with CL. The increased rates of urinary 8-OHdG excretion and the tubular expression of 8-OHdG produced by CsA treatment were reversed with CL treatment.


CONCLUSIONS
Thus, infiltrating macrophages were involved in both nonimmunologic and immunologic injury and led to apoptotic cell death in this rat model of chronic CsA nephropathy.
Ghee
Jung Yeon
JY
Department of Internal Medicine, Catholic University of Korea, Seoul 137-040, Korea.
Han
Dong He
DH
Song
Hyun Kuk
HK
Kim
Wan Young
WY
Kim
Su Hyun
SH
Yoon
Hye Eun
HE
Choi
Bum Soon
BS
Kim
Yong Soo
YS
Kim
Jin
J
Yang
Chul Woo
CW
D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease; D004002:Clodronic Acid / Q000008:administration & dosage; D016572:Cyclosporine / Q000633:toxicity*; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000293:injuries / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D007166:Immunosuppressive Agents; D008081:Liposomes; D004002:Clodronic Acid; D016572:Cyclosporine