MICROMouse Program Application Abstract
Long Chain Fatty Acids and Mineralocorticoid Receptor Upregulation in a Mouse Model of Diabetic Nephropathy
Bardia Askari (Seattle, WA)
Diabetic Nephropathy (DN) is a major microvascular complication of diabetes mellitus, affecting approximately 20-40% of all people diagnosed with diabetes and is the major cause of end stage renal disease. Progressive DN is most likely the result of a combination of environmental and genetic influences. However, the exact pathophysiologic mechanisms are not clearly delineated. Angiotensin II (Ang II), the main effector of the renin-angiotensin-aldosterone system (RAAS), has long been the main target of drug therapy. Pharmacologic monotherapy with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are major mainstays of drug treatment of DN. However, DN can continue to advance even in the presence of treatment. Recent studies have demonstrated that blockade of the mineralocorticoid receptor (MR), the main of target of aldosterone (ALDO) in the kidney, can have beneficial effect in the treatment of DN. ALDO has been shown to increase extracellular matrix production in non-renal tissues. The exact role of ALDO in the pathogenesis of DN is not known. Plasma long chain fatty acids (LCFA) are increased in obese patients and have been shown to contribute to type 2 diabetes. However, their contribution to DN is not well established. Our preliminary data show that in a mouse model of DN, plasma non-esterified free fatty acids are elevated and this increase is associated with increased expression of 11ß-HSD2 and MR mRNA in the renal cortex. We also have demonstrated, in a mouse mesangial cell line, that elevated concentrations of saturated and mono-unsaturated long chain fatty acids can increase the expression of 11ß-HSD2 and MR mRNA. We also observed that overexpression of Acsl1, an enzyme that activates LCFAs in cells, increased the expression 11ß-HSD2 and MR mRNA. Therefore, we conclude that the elevation of free fatty acids can increase the sensitivity of the mesangial cells to aldosterone by increasing the expression of MR, enhancing the pro-fibrotic effects of ALDO in the kidney.
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