Krüppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions

Divisiono of Intramural Research, Cell Biology Section, Laboratory of Experimental Pathology, Microarray Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709

^* To whom correspondence should be addressed. Email: jetten{at}niehs.nih.gov.

	Abstract

To obtain insight into the physiological functions of Krüppel-like zinc finger protein Gli-similar 2 (Glis2), mice deficient in Glis2 expression were generated. Glis2 mutant (Glis2^mut) mice exhibit a significantly shorter lifespan than littermate WT mice due to 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 is accompanied by infiltration of lymphocytic inflammatory cells and interstitial/glomerular fibrosis. The severity of the fibrosis, inflammatory infiltrates, and the 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. Comparison of the gene expression profiles of kidneys from 25/60 day-old WT and Glis2^mut mice by microarray analysis showed increased expression of many genes involved in immune responses/inflammation and fibrosis/tissue remodeling in kidneys of Glis2^mut mice, including several cytokines, adhesion and extracellular matrix proteins. Our data demonstrate that 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 the normal kidney architecture and functions.