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(American Journal of Pathology. 2003;163:2485-2494.)
© 2003 American Society for Investigative Pathology

Ischemia Induces Early Expression of a New Transcription Factor (6A3-5) in Kidney Vascular Smooth Muscle Cells

Studies in Rat and Human Renal Pathology

Gwenaële Garin^*, Chérif Badid, Brigitte McGregor, Madeleine Vincent, Sylviane Guerret^¶, Kazem Zibara^*, Adam Hurlstone^||, Maurice Laville and John L. McGregor^**

From INSERM XR331,^* EA 1582 Génomique Fonctionnelle de l’Athérothrombose, Faculté de Médecine Laënnec, Lyon, France; Service de Néphrologie, Hôpital Edouard Herriot, Lyon, France; EA 645, Faculté de Médecine Grange Blanche, Lyon, France; Service d’Anatomopathologie, Hôpital Edouard Herriot, Lyon, France; EA 3090,^¶Laboratoire des Biomatériaux, Faculté de Pharmacie, Lyon, France; Netherlands Institute for Developmental Biology,|| Hubrecht Laboratory, Utrecht, The Netherlands; Centre for Cardiovascular Biology and Medicine,^** King’s College, University of London, United Kingdom; and the Thrombosis Research Institute, Functional Genomics and Atherothrombosis Unit, London, United Kingdom

Acute renal failure, characterized by rapid decline in glomerular filtration rate, is a major cause of morbidity and mortality. During the evolution of renal diseases chronic ischemia develops. Indeed, acute or chronic renal failure may occur as a result of renal ischemia, which induces cells to dedifferentiate, proliferate, or become apoptotic. In this study, we have investigated the expression of a newly identified transcription factor, 6A3-5, under in vitro and in vivo conditions. Proliferating vascular smooth muscle were investigated in response to different mitogenic agents. The 6A3-5 expression was then studied in ischemic rat kidney, induced by renal pedicle clamping, followed, or not, by reperfusion. Subsequently human renal biopsies from early kidney grafts and chronic renal diseases were also investigated for 6A3-5 protein expression by immunohistochemistry. In vitro study shows an over-expression of 6A3-5 following 2 to 4 hours stimulation by serum or Angiotensin II, of rat proliferating aortic smooth muscle cell. Moreover, in vivo study shows that this new protein is over expressed in rat kidney submitted to 45 minutes ischemia. An anti-6A3-5 antibody shows the protein to be expressed in smooth muscle cells of the arterioles and intermediate size arteries, in mesangial cells and interstitial myofibroblasts. In human biopsies of early kidney grafts and renal disease, the same up-regulation of 6A3-5, as in acute ischemic situation, is observed. This 6A3-5 expression is intimately associated with -smooth muscle cell actin expression in mesangial cells, arteriolar smooth muscle cells as well as interstitial myofibroblasts. Transcription factor 6A3-5 could potentially be a novel early vascular marker of acute and chronic renal ischemic stress implicated in tissue remodeling.

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