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 decrease the tight associa...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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Nature Reviews Nephrology, Published online: 13 December 2019; doi:10.1038/s41581-019-0242-4A new study links pathogenic cubilin gene (CUBN) variants to proteinuria without progressive renal impairment, providing reassurance for a subset of patients, calling into question the accepted pathogenesis of glomerulosclerosis and suggesting future therapeutic options.
Source: Nature Reviews Nephrology - Category: Urology & Nephrology Authors: Source Type: research
Conclusion: A family history of diabetes in first-degree relatives is independently associated with a rapid decline in eGFR in the current relatively young studied patients. Our findings suggested that early diagnosis and treatment is important for these patients.
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
Clinical significance of urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in immunoglobulin A nephropathy
. Clin Nephrol. 2019 Dec 12;: Authors: Kim JS, Jeong KH Abstract AIMS: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes. Recently, it was reported that TWEAK may play an important role in the pathogenesis of kidney damage. In the present study, we investigated the role of TWEAK in immunoglobulin A nephropathy (IgAN). MATERIALS AND METHODS: The levels of serum TWEAK (sTWEAK) and urinary TWEAK ...
Source: Clinical Nephrology - Category: Urology & Nephrology Authors: Tags: Clin Nephrol Source Type: research
Publication date: Available online 11 December 2019Source: Pregnancy HypertensionAuthor(s): Anisha R. Bouter, Johannes J. DuvekotAbstractBackgroundIn 2018/2013 both ISSHP and ACOG revised their original statements and postulated new criteria for preeclampsia with and without severe features. Most importantly, preeclampsia can now also be established in the absence of proteinuria when other specific symptoms are present.ObjectiveWhat is the clinical impact of the use of three different new definitions for the diagnosis of preeclampsia?Study designRetrospective cohort study of all pregnant women who gave birth in the Erasmus...
Source: Pregnancy Hypertension: An International Journal of Womens Cardiovascular Health - Category: OBGYN Source Type: research
In this report, we focus on the correct diagnosis and management of renal irAEs, which remain controversial. PMID: 31813918 [PubMed - as supplied by publisher]
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
Authors: Itoh I, Kasuno K, Yamamoto C, Takahashi N, Shimizu H, Ojima T, Hayashi S, Kimura H, Iwano M Abstract Tofacitinib is a new small-molecule inhibitor of the JAK/STAT signaling pathway used to treat rheumatoid arthritis. We herein report a case of IgA vasculitis apparently caused by tofacitinib. A 67-year-old woman with rheumatoid arthritis developed IgA vasculitis after taking tofacitinib for 6 months. She presented with proteinuria and purpura of the lower extremities. Biopsy specimens from her skin and kidney were compatible with IgA vasculitis. Following termination of tofacitinib, the patient completely r...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
CONCLUSIONS Serum anti-PLA2R antibody, as determined by non-invasive technique, is a specific biomarker for diagnosis of IMN. Our results suggest that serum anti-PLA2R antibody has great potential to guide clinical diagnosis and treatment, as well as prognosis determination, in IMN patients. PMID: 31813930 [PubMed - in process]
Source: Medical Science Monitor - Category: Research Tags: Med Sci Monit Source Type: research
AbstractUrinary tract infection (UTI) is defined as the growth of a significant number of microorganisms of a single species in the urine, in the presence of symptoms. Symptoms in young children are non-specific such as fever without focus; young infants may manifest with irritability, failure to thrive, jaundice, vomiting and diarrhea. Older children usually have symptoms of cystitis or pyelonephritis. Symptoms of cystitis are dysuria, frequency, new onset incontinence and malodorous urine while symptoms of pyelonephritis are high grade fever, flank pain and vomiting. Rapid urine testing by microscopy for pus cells, dipst...
Source: Indian Journal of Pediatrics - Category: Pediatrics Source Type: research
We report a rare case of RPGN secondary to latent syphilis, which resolved with penicillin treatment in the absence of immunosuppressive therapy. A 28-year-old Black male with a history of HIV was evaluated for severe acute kidney injury, nephrotic-range proteinuria, and active urine sediment. Serologies for glomerulonephritis were negative. Rapid plasma reagin and treponema pallidum particle agglutination assay were reactive, confirming syphilis diagnosis. Kidney biopsy revealed focal and segmental necrotizing and crescentic lesion. Patient received weekly benzathine penicillin (PCN) for 3 weeks, and renal function improv...
Source: Clinical Nephrology - Category: Urology & Nephrology Authors: Tags: Clin Nephrol Source Type: research
ConclusionsBaseline diabetes may be independently associated with failure to achieve complete remission, but not with IMN relapse and renal function decline in IMN patients.
Source: International Urology and Nephrology - Category: Urology & Nephrology Source Type: research
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