MYH9 E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration

• Published in: Journal of the American Society of Nephrology 2018-01, Vol.29 (1), p.155-167
• Main Authors: Cechova, Sylvia, Dong, Fan, Chan, Fang, Kelley, Michael J, Ruiz, Phillip, Le, Thu H
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Albuminuria - genetics; Angiotensin II; Animals; Antihypertensive Agents - therapeutic use; Basic Research; Benzimidazoles - therapeutic use; Biphenyl Compounds; Blood Pressure - genetics; Cell Movement - genetics; Cells, Cultured; Disease Models, Animal; Genotype; Hypertension - chemically induced; Hypertension - genetics; Hypertension - physiopathology; Male; Mice; Mutation, Missense; Myosin Heavy Chains; Nephrectomy; Nonmuscle Myosin Type IIA - genetics; Podocytes - physiology; Podocytes - ultrastructure; Primary Cell Culture; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - pathology; Sodium Chloride, Dietary - administration & dosage; Stress Fibers - genetics; Tetrazoles - therapeutic use
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2015060707

Intronic variants of the gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease-associated nephropathy. However, the causal functional variants of have remained elusive. Rare missense mutations in cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type ( ) mice and mice heterozygous ( ) and homozygous ( ) for the mutation in each model, mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II-induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II-induced hypertension attenuated kidney disease development in mice. , isolated primary podocytes from mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that podocytes had the lowest migration rate, followed by then podocytes. In conclusion, the E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.