Deletion of Grem1 Causes Asymmetric Renal Development in Mice

Grem1 is a BMP antagonist implicated in fibrotic disease. Increased levels of Grem1 are detected in the kidney tubules of diabetic nephropathy patients, and correlate with progressive renal disease.. Grem1 was measured in 4 week old mice. Levels of Grem1 were highest in colon, brain and spleen with lower levels detected in kidney, liver, lung, stomach and skin. We generated grem1+/‐ mice on a mixed C57Bl/6J;FVBN background. Less than 5 % of viable offspring were grem1‐/‐, suggesting a significant number die at late developmental/early postnatal stage due to renal agenesis. The surviving grem1‐/‐ mice were smaller in size and weight compared to controls. Consistently, the right kidney was absent in grem1‐/‐ mice of both genders, with an enlarged left kidney evident. Glomerular density in this kidney in grem1‐/‐ mice was significantly lower than wild‐type mice (5.41 versus 9.26 gloms/mm 2 , p<0.001). However, the overall number of glomeruli was comparable between wild‐type and grem1‐/‐ mice, suggesting an expansion of the interstitial compartment as the cause of increased kidney size. Changes in renal function were present at 4 wk of age in grem1‐/‐ mice. Interestingly, levels of Grem2 and other BMP antagonists were altered in grem1‐/‐ kidney compared to wild‐type, suggesting compensatory changes may be occurring here.