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 have 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 of diabetic wild-type mice compared to littermate controls, particularly in kidney tubules. In contrast, diabetic grem1+/− mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared to age and sex-matched wild-type controls. Whereas the onset and induction of diabetes was 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 to wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type, but not grem1+/− kidney. Levels of pSmad1/5/8 decreased in wild-type, but not grem1+/− diabetic kidneys, suggesting that BMP signalling may be maintained in the absence of grem1.

Conclusions These data therefore identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.