Allelic depletion of grem1 attenuates diabetic kidney disease.

Sarah A. Roxburgh, J.J. Kattla, S.P. Curran, Yvonne M. O'Meara, Carol A. Pollock, Roel Goldschemding, Catherine Godson, Finian Martin, Derek P. Brazil

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53 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1641-1650
Number of pages10
JournalDiabetes
Volume58
Issue number7
DOIs
Publication statusPublished - Jul 2009

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

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    Roxburgh, S. A., Kattla, J. J., Curran, S. P., O'Meara, Y. M., Pollock, C. A., Goldschemding, R., Godson, C., Martin, F., & Brazil, D. P. (2009). Allelic depletion of grem1 attenuates diabetic kidney disease. Diabetes, 58(7), 1641-1650. https://doi.org/10.2337/db08-1365