Mouse Study Links Diabetes to Depressed ACE2 Activity

About one-third of patients with diabetes go on to develop kidney disease. Angiotensin-converting enzyme 2 is an exopeptidase that catalyzes the conversion of angiotensin I to the nonapeptide angiotensin[1-9]. ACE 2 has direct effects on cardiac function and is expressed predominantly in vascular endothelial cells of the heart and the kidneys.

Investigators at Northwestern University (Chicago, IL, USA) worked with a mouse diabetes model. They used immunohistologic techniques to demonstrate low levels of ACE2 in the glomeruli of the kidneys of diabetic mice as compared to a control group. When ACE2 activity was further decreased with an inhibitor drug, kidney disease worsened.

Results published in the November 2006 issue of the Journal of the American Society of Nephrology revealed that ACE2 was localized in the kidney podocytes, and that in the diabetic mice glomerular expression of ACE2 was reduced whereas glomerular ACE expression was increased. Podocytes are cells of the visceral epithelium in the kidneys and form a crucial component of the glomerular filtration barrier, contributing size selectivity and maintaining a massive filtration surface. Adjacent podocytes interlock to cover the basal lamina, which is intimately associated with the glomerular capillaries, but the podocytes leave gaps or thin filtration slits. The slits are covered by slit diaphragms, which are composed of a number of cell-surface proteins. Disruption of the slit diaphragms or destruction of the podocytes can lead to massive proteinuria where large amounts of protein are lost from the blood.

"ACE inhibitors are currently used to treat kidney disease,” said senior author Dr. Daniel Batlle, professor of medicine at Northwestern University. "An eventual ACE2 therapy, perhaps combined with ACE inhibitors could be doubly effective. This is a new frontier. Targeting the ACE2 enzyme may be important, much in the same way as the introduction of ACE inhibitors two decades ago to treat high blood pressure and slow the progression of kidney disease.”



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