Proteostasis as a therapeutic target in glomerular injury associated with mutant α-actinin-4.
Albert Yee,Joan Papillon,Julie Guillemette,Daniel R. Kaufman,Chris R. J. Kennedy,Andrey V. Cybulsky +5 more
TLDR
Treatment of mice with 4-PBA in the drinking water over a 10-wk period significantly reduced albuminuria and ER stress and chemical chaperones may represent a novel therapeutic approach to certain hereditary glomerular diseases.Abstract:
Mutations in α-actinin-4 (actinin-4) result in hereditary focal segmental glomerulosclerosis (FSGS) in humans. Actinin-4 mutants induce podocyte injury because of 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-phenylbutyrate (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 filamentous (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-wk 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 decrease the tight association of actinin-4 K256E with F-actin and did not reduce albuminuria in actinin-4 K256E transgenic mice. Thus, chemical chaperones, such as 4-PBA, may represent a novel therapeutic approach to certain hereditary glomerular diseases.read more
Citations
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Chemical and biological approaches synergize to ameliorate protein-folding diseases
TL;DR: It is demonstrated that the innate cellular protein homeostasis capacity can be enhanced to fold mutated enzymes that would otherwise misfold and be degraded, using small molecule proteostasis regulators.
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The ubiquitin–proteasome system in kidney physiology and disease
TL;DR: The ubiquitin–proteasome system selectively degrades the majority of the intracellular proteins in an ATP-consuming manner and closely interacts with the autophagosomal–lysosomal system in physiological and pathophysiological situations.
Journal ArticleDOI
From podocyte biology to novel cures for glomerular disease.
Elena Torban,Fabian Braun,Nicola Wanner,Tomoko Takano,Paul Goodyer,Rachel Lennon,Pierre Ronco,Andrey V. Cybulsky,Tobias B. Huber +8 more
TL;DR: A review briefly highlights recent advances made in understanding podocyte structure and metabolism, experimental systems in which to study podocytes and glomerular disease, disease mediators, genetic and immune origins of glomerulopathies, and the development of novel therapeutic agents to protect podocyte and glomersular injury.
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Review: ER stress-induced cell death in osteoarthritic cartilage.
TL;DR: Current knowledge about the biogenesis of ECM components in chondrocytes is provided, possible causes for the impairment of involved processes are described and attention is focused on the ER stress-induced cell death in articular cartilage during OA.
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FKN Facilitates HK-2 Cell EMT and Tubulointerstitial Lesions via the Wnt/β-Catenin Pathway in a Murine Model of Lupus Nephritis.
TL;DR: The data indicate that FKN plays essential roles in the EMT progression and development of TIL in MRL/lpr mice, most likely through activation of the Wnt/β-catenin signaling pathway.
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