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Molecular and Cellular Biology, April 2008, p. 2358-2367, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01722-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Krüppel-Like Zinc Finger Protein Glis2 Is Essential for the Maintenance of Normal Renal Functions ^,

Yong-Sik Kim,¹ Hong Soon Kang,¹ Ronald Herbert,² Ju Youn Beak,¹ Jennifer B. Collins,³ Sherry F. Grissom,³ and Anton M. Jetten^1*

Division of Intramural Research, Cell Biology Section,¹ Laboratory of Experimental Pathology,² and Microarray Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709³

Received 19 September 2007/ Returned for modification 22 October 2007/ Accepted 20 January 2008

To obtain insight into the physiological functions of the Krüppel-like zinc finger protein Gli-similar 2 (Glis2), mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2^mut) mice exhibit significantly shorter life spans than do littermate wild-type (WT) mice due to the development of progressive chronic kidney disease with features resembling nephronophthisis. Glis2^mut mice develop severe renal atrophy involving increased cell death and basement membrane thickening in the proximal convoluted tubules. This development is accompanied by infiltration of lymphocytic inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and glomerular and tubular changes progresses with age. Blood urea nitrogen and creatinine increase, and Glis2^mut mice develop proteinuria and ultimately die prematurely of renal failure. A comparison of the gene expression profiles of kidneys from 25-day-old/60-day-old WT and Glis2^mut mice by microarray analysis showed increased expressions of many genes involved in immune responses/inflammation and fibrosis/tissue remodeling in kidneys of Glis2^mut mice, including several cytokines and adhesion and extracellular matrix proteins. Our data demonstrate that a deficiency in Glis2 expression leads to tubular atrophy and progressive fibrosis, similar to nephronophthisis, that ultimately results in renal failure. Our study indicates that Glis2 plays a critical role in the maintenance of normal kidney architecture and functions.

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* Corresponding author. Mailing address: Division of Intramural Research, Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709. Phone: (919) 541-2768. Fax: (919) 541-4133. E-mail: jetten{at}niehs.nih.gov

Published ahead of print on 28 January 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, April 2008, p. 2358-2367, Vol. 28, No. 7
0270-7306/08/$08.00+0     doi:10.1128/MCB.01722-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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