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Activation of intrarenal complement system in mouse model for chronic cyclosporine nephrotoxicity
Young Ok Kim1, Sun Woo Lim, Can Li
1Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Purpose:
Local activation of the complement system plays a role in target organ damage. The aim of our study was to investigate the influence of cyclosporine (CsA)- induced renal injury on the complement system in the kidney.
Materials And Methods:
Mice fed a low salt (0.01%) diet were treated with vehicle (VH, olive oil, 1 mL/kg/day) or CsA (30 mg/kg/day) for one or four weeks. Induction of chronic CsA nephrotoxicity was evaluated with renal function and histomorphology. Activation of the complement system was assessed through analysis of the expression of C3, C4d, and membrane attack complex (MAC), and the regulatory proteins, CD46 and CD55. CsA treatment induced renal dysfunction and typical morphology (tubulointerstitial inflammation and fibrosis) at four weeks.
Results:
CsA-induced renal injury was associated with increased the expression of C3, C4d, and MAC (C9 and upregulation of complement regulatory proteins (CD 46 and CD55). Immunohistochemistry revealed that the activated complement components were mainly confined to the injured tubulointerstitium.
Conclusion:
CsA-induced renal injury is associated with activation of the intrarenal complement system.
Insights
Cyclosporine (CsA) causes kidney damage by activating the intrarenal complement system. This activation involves complement components like C3, C4d, and MAC, and regulatory proteins.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- The complement system is crucial in immune responses and can contribute to organ damage.
- Cyclosporine (CsA) is an immunosuppressant known to cause kidney injury.
Purpose of the Study:
- To investigate how CsA-induced renal injury affects the complement system within the kidney.
- To determine the role of intrarenal complement activation in CsA nephrotoxicity.
Main Methods:
- Mice were administered CsA or vehicle for one or four weeks on a low-salt diet.
- Renal function and histomorphology were assessed to evaluate CsA nephrotoxicity.
- Complement activation markers (C3, C4d, MAC) and regulatory proteins (CD46, CD55) were analyzed.
Main Results:
- CsA treatment led to renal dysfunction, tubulointerstitial inflammation, and fibrosis at four weeks.
- Increased expression of C3, C4d, and MAC (C9) was observed in CsA-treated kidneys.
- Upregulation of complement regulatory proteins CD46 and CD55 occurred, with activated components localized to injured areas.
Conclusions:
- CsA-induced renal injury is linked to the activation of the complement system within the kidney.
- Intrarenal complement activation may play a significant role in the pathogenesis of CsA nephrotoxicity.
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