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From Bedside to Bench Drug-induced Tubulointerstitial Disease Cyclosporine Nephropathy Study from Models of Cultured Renal Epithelial Cells

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Author(s): Mai-Szu Wu

Journal: Chang Gung Medical Journal
ISSN 2072-0939

Volume: 30;
Issue: 01;
Start page: 7;
Date: 2007;
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Keywords: cyclosporine | nitric oxide | ion transport | renin-angiotensin system | renal epithelial cells

ABSTRACT
Cyclosporine (CsA) is a potent immunosuppressant used in the prevention of transplantedorgan 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 decreasedthe expression iNOS and production of the nitric oxide (NO) in mouse medullary thickascending limbs (mTAL) cells. The alteration might subsequently affect the renal medullaryhemodynamics and play a role in development of CsA nephrotoxicity. CsA decreased basolateralNa+-K+ ATPase and increased apical Na+-K+-Cl- co-transport activity. The effectsmight subsequently account for the CsA-associated sodium retention, and decreased NOproduction. Decreased Na+-K+ ATPase activity and enhanced Na+-K+-Cl- co-transport activitywere the presentations of renal cell de-differentiation and proliferation. CsA increasedmTAL cell proliferation by 2-fold and suggested the proliferation effect of CsA on renalepithelial cells. Activation of the renin-angiotensin system (RAS) is associated with renalfibrosis and progression of the renal failure. CsA enhanced intrarenal RAS activity mainlythrough the activation of the AT1 receptor by increasing the receptor numbers. The resultssuggest the role of the AT1 receptor antagonist in treating CsA nephrotoxicity. CsA alsodecreased the inflammation related intrarenal prostglandin production via COX-2 production.Taken together, CsA altered cell proliferation, ionic transport, NO production, RAS andprostaglandins production in renal epithelial cells. The alterations were correlative and interactiveto each other. The comprehension of the effect of CsA in renal epithelial cells gives usmore insight in understanding drug-induced renal tubulointerstitial disease.
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