Allelic Depletion of grem1 Attenuates Diabetic Kidney Disease
- Sarah A. Roxburgh1,
- Jayesh J. Kattla1,
- Simon P. Curran1,
- Yvonne M. O'Meara1,2,
- Carol A. Pollock3,
- Roel Goldschmeding4,
- Catherine Godson1,
- Finian Martin5 and
- Derek P. Brazil1
- 1University College Dublin Diabetes Research Centre, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland;
- 2Mater Misericordiae University Hospital, University College Dublin Conway Institute, University College Dublin, Belfield, Dublin, Ireland;
- 3Kolling Institute, University of Sydney, New South Wales, Australia;
- 4Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands;
- 5School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland.
- Corresponding author: Derek P. Brazil, derek.brazil{at}ucd.ie.
Abstract
OBJECTIVE Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy.
RESEARCH DESIGN AND METHODS Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1+/−) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes.
RESULTS A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1+/− mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1+/− and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1+/− mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type but not in grem1+/− kidneys. Levels of pSmad1/5/8 decreased in wild-type but not in grem1+/− diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1.
CONCLUSIONS These data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.
Footnotes
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- Received October 5, 2008.
- Accepted April 9, 2009.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2009 by the American Diabetes Association.
