Abstract 355: MYH9 E1841K Mutation Enhances Susceptibility to Angiotensin-II Induced Proteinuria and Podocyte Injury That is Ameliorated by AT1 Receptor Inhibition.
The MYH9 gene encodes the nonmuscle myosin heavy chain IIA. Recent genome-wide association studies (GWAS) demonstrated that intronic variants of the MYH9 gene are associated with non-diabetic kidney disease and hypertension-attributed ESRD in African-Americans. However, the causal functional variants of MYH9 have remained elusive. Rare autosomal-dominant missense mutations in MYH9 cause macrothrombocytopenia, and are occasionally associated with development of nephropathy. The E1841K mutation is the most common MYH9 missense mutation and has been associated with nephropathy in some carriers. To determine the role of the MYH9 E1841K mutation in the development of kidney disease, we studied a mouse line carrying the E1841K mutation. On a mixed genetic background (129S6 and C57BL/6), there was no difference in systolic blood pressure (SBP) between wild-type (WT, -/-) and mice with the E1841K mutation (designated as E1841K (+): +/- and/or +/+) at baseline or after high salt diet (HSD,6 % NaCl). There was also no difference in albumin/creatinine (A/C ratio) at baseline or after HSD between groups. We next assessed the effects of the E1841K mutation in response to angiotensin II (Ang II) infusion @1000 ng/kg/min for 28 days via mini-osmotic pump. Despite similar increases in SBP after Ang II (WT 197 ± 4 mm Hg, n=15; E1841K +/- 197 ± 3 mm Hg, n=9; E1841K +/+ 199 ± 5 mm Hg; n=6), E1841K(+) mice displayed severe proteinuria in a dose-dependent manner (A/C ratio (ug/mg): WT 806±94, E1841K +/- 1341±293, E1841K +/+ 2209± 366, p=0.001, ANOVA ). By light microscopy, WT mice had only mild mesangial expansion, whereas E1841K +/+ mice had focal segmental glomerulosclerosis and large amounts of proteinaceous casts. By electron microscopy, WT mice had intact podocytes, whereas, E1841K +/+ mice displayed severe podocyte foot process effacement/fusion. Treatment of E1841K (+) mice with candesartan, an angiotensin type 1 receptor (AT1R) inhibitor, significantly prevented Ang II-induced hypertension and proteinuria (E1841K (+) (n=6; +/- (n=4) and +/+ (n=2)): SBP = 138 ± 4 mm Hg, A/C ratio = 111 ± 47 ug/mg; p ≤ 0.0001 vs. untreated), and ameliorated podocyte foot process effacement in E1841K +/+ mice. In conclusion, the MYH9 E1841K mutation predisposes to AT1R mediated podocyte injury.
- © 2012 by American Heart Association, Inc.