Diabetes 2013 May (2)-2

Attenuation of a novel kidney glycogen storage disease known as Armanni–Ebstein lesions by a new anti-fibrotic, anti-inflammatory agent, FT011

Diabetologia. 2013 Mar;56(3):675-9

X. Lau & Y. Zhang & D. J. Kelly & D. I. Stapleton

Diabetes mellitus is associated with microvascular complications including cardiomyopathy and nephropathy with persistent hyperglycemia. Diabetic nephropathy is associated with progressive kidney dysfunction and is the leading cause of end stage kidney disease. A key morphological and unexplained change associated with sustained hyperglycemia in the diabetic kidney is the accumulation of glycogen known as Armanni-Ebstein lesions that was first identified in 1877.

To understand the molecular basis of the Armanni-Ebstein lesions we measured glycogen concentration, glycogen synthase and glycogen phosphorylase enzyme activities, mRNA and protein expression levels of glycogenin in kidney lysates from control and a transgenic (mRen-2)27 rat models of diabetes. Both control and diabetic rats were treated with and without a new anti-fibrotic agent called FT011 that we found attenuated the Armanni-Ebstein lesions in the diabetic rat.

The results shown that diabetic nephropathy was associated with increased glycogen content, increased glycogen synthase activity and decreased glycogen phosphorylase activity. Glycogenin, the core protein within each glycogen particle, had increased mRNA and very high protein expression levels compared with control kidneys. Treatment with FT011 did not change glycogen synthase or glycogen phosphorylase enzyme activities but prevented both glycogenin mRNA synthesis and accumulation of Armanni-Ebstein lesions in the diabetic kidney.

In conclusion, Armanni-Ebstein lesions found in diabetic nephropathy are due to the aberrant expression of glycogenin at both mRNA and protein levels, providing an explanation for the increased glycogen concentration found within the diabetic kidney. FT011 treatment, already known to reduce renal and cardiac fibrosis, also reduced glycogenin expression and subsequently renal glycogen concentration in rats with diabetic nephropathy.

Supplement picture:

David ian stapleton-new

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