Cyclosporine A inhibits the adaptive responses to hypertonicity: a potential mechanism of nephrotoxicity.
Cell survival in the hypertonic environment of the renal medulla is dependent on the intracellular accumulation of protective organic solutes through the induction of genes whose transcriptional regulation is mediated in part by interaction between osmotic response elements and the transcription nuclear factor of activated T lymphocyte 5. It is shown that cyclosporine A (CsA) prevents the nuclear translocation of the transcription nuclear factor of activated T lymphocyte 5 and inhibits osmotic response element-mediated reporter gene expression. The expression of mRNA for hypertonicity-induced genes (aldose reductase, betaine/gamma-amino-n-butyric acid transporter 1, and heat shock protein 70) is also decreased in the medulla of CsA-treated rats. CsA inhibits the increase of betaine/gamma-amino-n-butyric acid transporter 1 and heat shock protein 70 mRNA in osmotically stressed MDCK cells, blocks cell proliferation under isotonic conditions, and augments hypertonicity-induced apoptosis. Histologic examination of the kidneys of CsA-treated rats shows a marked increase in apoptosis in the renal medulla where hypertonicity normally prevails. The data are consistent with calcineurin-mediated induction of hypertonic stress-response genes, and they suggest that CsA nephrotoxicity may in part result from inhibition of the adaptive responses to hypertonicity occurring during the urinary concentrating mechanism.
Sheikh-Hamad
David
D
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Nadkarni
Varsha
V
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Choi
Yeong-Jin
YJ
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Truong
Luan D
LD
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Wideman
Christi
C
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Hodjati
Ramin
R
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Gabbay
Kenneth H
KH
*Renal Section, Department of Medicine, Department of Pathology, and the Harry B. and Aileen Gordon Diabetes Research Laboratory, Molecular Diabetes and Metabolism Section, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004285:Dogs; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D006982:Hypertonic Solutions / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced*; D007679:Kidney Medulla / Q000378:metabolism / Q000502:physiology; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D050778:NFATC Transcription Factors; D009997:Osmotic Pressure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000502:physiology
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D006982:Hypertonic Solutions; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D014157:Transcription Factors; D016572:Cyclosporine; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases