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Author Notes:

Address for reprint requests and other correspondence: H.-P. Ma, Dept. of Physiology, Emory Univ. School of Medicine, 615 Michael ST, Suite 601, Atlanta, GA 30322 (e-mail: heping.ma@emory.edu).

B.-C. Liu, X. Song, and X.-Y. Lu contributed equally to this work.

Author contributions: B.-C.L., X.S., X.-Y.L., and S.-P.W. performed experiments; B.-C.L. and C.F. analyzed data; B.-C.L. prepared figures; A.A.A., D.C.E., B.-Z.S., X.-Q.L., and H.-P.M. approved final version of manuscript; H.-P.M. conception and design of research; H.-P.M. interpreted results of experiments; H.-P.M. drafted manuscript; H.-P.M. edited and revised manuscript.

No conflicts of interest, financial or otherwise, are declared by the author(s).

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Research Funding:

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant 5R01-DK-067110 (to H.-P. Ma) and by National Natural Science Foundation of China Project 81130028 (to B.-Z. Shen).

Keywords:

  • transepithelial resistance
  • scanning ion conductance microscopy
  • confocal microscopy
  • zonula occludens-1
  • cholesterol
  • kidney injury
  • reactive oxygen species

Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells

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Journal Title:

American Journal of Physiology - Renal Physiology

Volume:

Volume 305, Number 3

Publisher:

, Pages F304-F313

Type of Work:

Article | Post-print: After Peer Review

Abstract:

We used mouse cortical collecting duct principal cells (mpkCCDc14 cell line) as a model to determine whether statins reduce the harmful effects of cyclosporine A (CsA) on the distal nephron. The data showed that treatment of cells with CsA increased transepithelial resistance and that the effect of CsA was abolished by lovastatin. Scanning ion conductance microscopy showed that CsA significantly increased the height of cellular protrusions near tight junctions. In contrast, lovastatin eliminated the protrusions and even caused a modest depression between cells. Western blot analysis and confocal microscopy showed that lovastatin also abolished CsA-induced elevation of both zonula occludens-1 and cholesterol in tight junctions. In contrast, a high concentration of CsA induced apoptosis, which was also attenuated by lovastatin, elevated intracellular ROS via activation of NADPH oxidase, and increased the expression of p47phox. Sustained treatment of cells with lovastatin also induced significant apoptosis, which was attenuated by CsA, but did not elevate intracellular ROS. These results indicate that both CsA and lovastatin are harmful to principal cells of the distal tubule, but via ROS-dependent and ROS-independent apoptotic pathways, respectively, and that they counteract probably via mobilization of cellular cholesterol levels.

Copyright information:

© 2013 the American Physiological Society

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