Macrophage depletion attenuates chronic cyclosporine A nephrotoxicity.
BACKGROUND
Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized by renal dysfunction and interstitial fibrosis. Early and progressive renal macrophage influx, correlating with latter interstitial fibrotic areas, has been associated with CsA treatment. This study investigated the role of macrophages, the nitric oxide (NO) pathway, and the oxidative stress on chronic CsA nephrotoxicity.


METHODS
The macrophages were depleted by clodronate liposomes. Animals were distributed into four groups: vehicle (olive oil for 21 days), CsA 7.5 mg/kg per day (21 days), CsA plus clodronate (5 mg/mL intraperitoneally on days -4, 1, 4, 11, and 18 of CsA treatment), or vehicle plus clodronate. On day 22, glomerular filtration rate, renal blood flow, renal tubulointerstitial fibrosis, CsA blood levels, serum malondialdehyde and renal tissue immunohistochemistry for macrophages, inducible NO synthase, transforming growth factor-beta, nuclear factor-kbeta, alpha-smooth muscle actin, vimentin, and nitrotyrosine were assessed.


RESULTS
CsA-induced increase in the macrophage was prevented by clodronate. Macrophage depletion attenuated the reductions in the glomerular filtration rate and renal blood flow, the development of tubulointerstitial fibrosis, malondialdehyde increase and increases in nuclear factor-kbeta, transforming growth factor-beta, vimentin, inducible NO synthase, and nitrotyrosine expression provoked by CsA. Clodronate did not affect alpha-smooth muscle actin expression and CsA blood levels.


CONCLUSIONS
Renal macrophage influx plays an important role in CsA-induced chronic nephrotoxicity. The NO pathway and oxidative stress are likely mechanisms involved in the genesis of this form of renal injury.
Division of Nephrology, São Jose do Rio Preto Medical School, São Jose do Rio Preto, SP, Brazil.
Carla P
CP
Carlos
Glória E F
GE
Mendes
André R
AR
Miquelin
Marcus A M
MA
Luz
Cleonice G A
CG
da Silva
Nico
N
van Rooijen
Terezila M
TM
Coimbra
Emmanuel A
EA
Burdmann
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004002:Clodronic Acid / Q000494:pharmacology*; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D007677:Kidney Function Tests; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000276:immunology; D014655:Vascular Resistance / Q000187:drug effects; D014746:Vimentin / Q000276:immunology
D000906:Antibodies; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D014746:Vimentin; D004002:Clodronic Acid; D009569:Nitric Oxide; D014443:Tyrosine; D016572:Cyclosporine