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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Publication date: Available online 10 October 2020Source: American Journal of Kidney DiseasesAuthor(s): Shreeram Akilesh, Cynthia C. Nast, Michifumi Yamashita, Kammi Henriksen, Vivek Charu, Megan L. Troxell, Neeraja Kambham, Erika Bracamonte, Donald Houghton, Naila I. Ahmed, Chyi Chyi Chong, Bijin Thajudeen, Shehzad Rehman, Firas Khoury, Jonathan E. Zuckerman, Jeremy Gitomer, Parthassarathy C. Raguram, Shanza Mujeeb, Ulrike Schwarze, M. Brendan Shannon
Source: American Journal of Kidney Diseases - Category: Urology & Nephrology Source Type: research
We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN. PMID: 33028760 [PubMed - in process]
Source: The Tohoku Journal of Experimental Medicine - Category: Research Authors: Tags: Tohoku J Exp Med Source Type: research
Abstract Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease is induced by antibodies, which are directed against the podocyte protein phospholipase A2 receptor 1 (PLA2R1-ab) in 80% of cases. B cell depleting treatments, most notably rituximab, a chimeric CD20-antibody, are often effective for treatment of MN. However, in 35-40% of patients rituximab fails to induce remission of disease and relapses after rituximab-induced remission are frequent. Therefore, alternative treatment options are necessary. Over the past years optimized antibodies targeting CD20 were designed to ov...
Source: Journal of Nephrology - Category: Urology & Nephrology Authors: Tags: J Nephrol Source Type: research
We report a patient with HSP who presented with cutaneous ulcerative plaques and proteinuria in the setting of warfarin therapy. We would like to raise the awareness of this potential adverse effect of warfarin for prompt diagnosis.
Source: Dermatology Online Journal - Category: Dermatology Source Type: research
Abstract BACKGROUND: The prevalence of kidney involvement during SARS-CoV-2 infection has been reported to be high. Nevertheless, data are lacking about the determinants of acute kidney injury (AKI) and the combined effect of chronic kidney disease (CKD) and AKI in COVID-19 patients. METHODS: We collected data on patient demographics, comorbidities, chronic medications, vital signs, baseline laboratory test results and in-hospital treatment in patients with COVID-19 consecutively admitted to our Institution. Chronic kidney disease was defined as eGFR 
Source: Journal of Nephrology - Category: Urology & Nephrology Authors: Tags: J Nephrol Source Type: research
Glomerular endothelial cell (GEnC) dysfunction is important in the pathogenesis of glomerular sclerotic diseases, including Focal Segmental Glomerulosclerosis (FSGS) and overt diabetic nephropathy (DN). GEnCs form the first cellular barrier in direct contact with cells and factors circulating in the blood. Disturbances in these circulating factors can induce GEnC dysfunction. GEnC dysfunction occurs in early stages of FSGS and DN, and is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transit...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
CONCLUSION: Interlaboratory bias was lower for urinary albumin measurement compared to urinary proteins in hypertensive women evaluated for preeclampsia. Better harmonization with the use of albumin instead of protein measurement would reduce instances where results of different laboratories lead to opposite diagnosis of kidney damage in pregnancy. PMID: 33031818 [PubMed - as supplied by publisher]
Source: Clinical Biochemistry - Category: Biochemistry Authors: Tags: Clin Biochem Source Type: research
Abstract Afferent renal nerves exhibit a dual function controlling central sympathetic outflow via afferent electrical activity and influencing intrarenal immunological processes by releasing peptides such as calcitonin-gene-related peptide (CGRP). We tested the hypothesis that increased afferent (ARNA) and efferent renal nerve activity (RSNA) occur with augmented release of CGRP in anti-Thy1.1 nephritis, in which enhanced CGRP release exacerbates inflammation. Nephritis was induced in Sprague-Dawley rats by intravenous injection of OX-7 antibody (1.75 mg/kg), animals were investigated neurophysiologically, electr...
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research
Authors: Muro K, Toda N, Yamamoto S, Yanagita M Abstract Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and protein...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
Abstract OBJECTIVE: Preeclampsia (PE) is a pregnancy-associated condition initiated by placental factors. We have demonstrated that placental extracellular vesicles (pcEVs) cause hypertension and proteinuria in pregnant and non-pregnant mice. STUDY DESIGN: An observational study with both case-control and longitudinal designs. SETTING: A single center at the Department of Obstetrics and Gynecology, Tianjin Medical University. POPULATION: We collected blood samples and clinical information from 54 PE patients, 33 normally pregnant women with at 30-36 gestational weeks and on postpartum days 1 and 4 f...
Source: BJOG : An International Journal of Obstetrics and Gynaecology - Category: OBGYN Authors: Tags: BJOG Source Type: research
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