From bedside to bench drug-induced tubulointerstitial disease cyclosporine nephropathy study from models of cultured renal epithelial cells

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Abstract

Cyclosporine (CsA) is a potent immunosuppressant used in the prevention of transplanted organ rejection. CsA is associated with sodium retention, hypertension, hyperkalemia, interstitial fibrosis, and progressive renal failure in transplant recipients. The cellular mechanisms, responding to these complications, were revealed in recent studies. CsA decreased the expression iNOS and production of the nitric oxide (NO) in mouse medullary thick ascending limbs (mTAL) cells. The alteration might subsequently affect the renal medullary hemodynamics and play a role in development of CsA nephrotoxicity. CsA decreased basolateral Na +-K + ATPase and increased apical Na +-K +-Cl - co-transport activity. The effects might subsequently account for the CsA-associated sodium retention, and decreased NO production. Decreased Na +-K + ATPase activity and enhanced Na +-K +-Cl - co-transport activity were the presentations of renal cell de-differentiation and proliferation. CsA increased mTAL cell proliferation by 2-fold and suggested the proliferation effect of CsA on renal epithelial cells. Activation of the renin-angiotensin system (RAS) is associated with renal fibrosis and progression of the renal failure. CsA enhanced intrarenal RAS activity mainly through the activation of the AT 1 receptor by increasing the receptor numbers. The results suggest the role of the AT 1 receptor antagonist in treating CsA nephrotoxicity. CsA also decreased the inflammation related intrarenal prostglandin production via COX-2 production. Taken together, CsA altered cell proliferation, ionic transport, NO production, RAS and prostaglandins production in renal epithelial cells. The alterations were correlative and interactive to each other. The comprehension of the effect of CsA in renal epithelial cells gives us more insight in understanding drug-induced renal tubulointerstitial disease.

Original languageEnglish
Pages (from-to)7-16
Number of pages10
JournalChang Gung Medical Journal
Volume30
Issue number1
Publication statusPublished - Jan 2007
Externally publishedYes

Keywords

  • Cyclosporine
  • Ion transport
  • Nitric oxide
  • Renal epithelial cells
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Medicine(all)

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