Proteostasis as a Therapeutic Target in Glomerular Injury Associated with Mutant Alpha-Actinin-4.

Proteostasis as a Therapeutic Target in Glomerular Injury Associated with Mutant Alpha-Actinin-4.
Am J Physiol Renal Physiol. 2018 Jun 06;:
Authors: Yee A, Papillon J, Guillemette J, Kaufman DR, Kennedy CRJ, Cybulsky AV
Abstract
Mutations in alpha-actinin-4 (actinin-4) result in hereditary focal segmental glomerulosclerosis (FSGS) in humans. Actinin-4 mutants induce podocyte injury due to dysregulation of the cytoskeleton and proteotoxicity. Injury may be associated with endoplasmic reticulum (ER) stress and polyubiquitination of proteins. We assessed if the chemical chaperone, 4-phenylbutyric acid (4-PBA) can ameliorate the proteotoxicity of an actinin-4 mutant. Actinin-4 K255E, which causes FSGS in humans (K256E in the mouse), showed enhanced ubiquitination, accelerated degradation, aggregate formation, and enhanced association with F-actin in glomerular epithelial cells (GECs). The mutant disrupted ER function and stimulated autophagy. 4-PBA reduced actinin-4 K256E aggregation and its tight association with F-actin. Transgenic mice that express actinin-4 K256E in podocytes develop podocyte injury, proteinuria and FSGS, in association with glomerular ER stress. Treatment of these mice with 4-PBA in the drinking water over a 10 week period significantly reduced albuminuria and ER stress. Another drug, celastrol, which enhanced expression of ER and cytosolic chaperones in GECs tended to reduce actinin-4 aggregation, but did not decre...

Source: Am J Physiol Renal P... - June 6, 2018 Category: Urology & Nephrology Authors: Yee A, Papillon J, Guillemette J, Kaufman DR, Kennedy CRJ, Cybulsky AV Tags: Am J Physiol Renal Physiol Source Type: research