ORCID Profile
0000-0002-9106-2324
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
DOI: 10.1038/S41419-021-03688-7
Abstract: Kidney disease progression can be affected by Na + abundance. A key regulator of Na + homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na + transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na + induced damage remain poorly understood. Here we show that a high Na + diet compromised kidney function in Nedd4-2 -deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na + rescued kidney disease in Nedd4-2 -deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na + homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 17-02-2012
DOI: 10.1038/CDD.2012.13
Publisher: Wiley
Date: 10-07-2008
DOI: 10.1111/J.1365-2605.2007.00789.X
Abstract: Selenium (Se) is essential for male fertility. The present study was carried out to observe the defects associated with Se deficiency as well as excess Se supplementation by analyzing the sperm ultrastructure and chromatin organization. Different Se status mice were generated viz. Se deficient (group I), Se adequate (group II) and Se excess (group III) by feeding the respective diets for a period of 4 (group Ia, IIa and IIIa) and 8 weeks (group Ib, IIb and IIIb). Reduction in sperm concentration, motility and percentage fertility was observed in Se deficient and Se excess groups. Electron microscopy revealed mitochondrial swelling and gaps between adjacent mitochondria in mice fed Se-deficient diet for 4 weeks. At 8 weeks, several abnormalities such as loose contact of the mitochondrial helix with the plasma membrane, loss of mitochondria, retention of cytoplasmic droplet, fracturing of outer dense fibres and presence of both the midpiece and the principal piece cross-sections in a common plasma membrane were observed. In Se excess group, the predominant defect was the frequent presence of equidistant, cross-sectioned midpieces of the tail embedded in a common cytoplasm. These defects are indicative of loss of sperm motility. Spermatozoa from Se-deficient mice had incompletely condensed chromatin and indicated an increase in occurrence of DNA strand breaks. The animals fed Se excess diet also indicated increase in DNA breaks but this was significantly less than the deficient diet fed groups. Our study reveals the defects associated with Se deficiency that result in loss of reproductive ability and also reflects its possible harmful effects on spermatozoa after prolonged consumption at supranutritional level.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2015
Abstract: Ageing is a complex biological process for which underlying biochemical changes are still largely unknown. We performed comparative profiling of the cellular proteome and metabolome to understand the molecular basis of ageing in Caspase-2- deficient ( Casp2 −/− ) mice that are a model of premature ageing in the absence of overt disease. Age-related changes were determined in the liver and serum of young (6–9 week) and aged (18–24 month) wild-type and Casp2 −/− mice. We identified perturbed metabolic pathways, decreased levels of ribosomal and respiratory complex proteins and altered mitochondrial function that contribute to premature ageing in the Casp2 −/− mice. We show that the metabolic profile changes in the young Casp2 −/− mice resemble those found in aged wild-type mice. Intriguingly, aged Casp2 −/− mice were found to have reduced blood glucose and improved glucose tolerance. These results demonstrate an important role for caspase-2 in regulating proteome and metabolome remodelling during ageing.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2020
DOI: 10.1038/S41418-019-0468-5
Abstract: Salt homeostasis is maintained by tight control of Na + filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na + channel (ENaC), which is rate-limiting for Na + reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na + exacerbated kidney injury in Nedd4-2 -deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na + resulted in reduced levels of ENaC. However, Nedd4-2 -deficient kidneys maintained elevated ENaC even after high dietary Na + , suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na + significantly ameliorated nephropathy in Nedd4-2 -deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2 -deficient mice is sensitive to dietary Na + , which may have implications in the management of disease in patients with kidney disease.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2014
DOI: 10.1038/ONC.2014.413
Abstract: Caspase-2 belongs to the caspase family of cysteine proteases with established roles in apoptosis. Recently, caspase-2 has been implicated in nonapoptotic functions including maintenance of genomic stability and tumor suppression. Our previous studies demonstrated that caspase-2 also regulates cellular redox status and delays the onset of several ageing-related traits. In the current study, we tested stress tolerance ability in caspase-2-deficient (Casp2(-/-)) mice by challenging both young and old mice with a low dose of the potent reactive oxygen species (ROS) generator, PQ that primarily affects lungs. In both groups of mice, PQ induced pulmonary damage. However, the lesions in caspase-2 knockout mice were consistently and reproducibly more severe than those in wild-type (WT) mice. Furthermore, serum interleukin (IL)-1β and IL-6 levels were higher in PQ-exposed aged Casp2(-/-) mice indicating increased inflammation. Interestingly, livers from Casp2(-/-) mice displayed karyomegaly, a feature commonly associated with ageing and aneuploidy. Given that Casp2(-/-) mice show impaired antioxidant defense, we tested oxidative damage in these mice. Protein oxidation significantly increased in PQ-injected old Casp2(-/-) mice. Moreover, FoxO1, SOD2 and Nrf2 expression levels were reduced and induction of superoxide dismutase (SOD) and glutathione peroxidase activity was not observed in PQ-treated Casp2(-/-) mice. Strong c-Jun amino-terminal kinase (JNK) activation was observed in Casp2(-/-) mice, indicative of increased stress. Together, our data strongly suggest that caspase-2 deficiency leads to increased cellular stress largely because these mice fail to respond to oxidative stress by upregulating their antioxidant defense mechanism. This makes the mice more vulnerable to exogenous challenges and may partly explain the shorter lifespan of Casp2(-/-) mice.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2014
Publisher: Public Library of Science (PLoS)
Date: 10-03-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 18-11-2013
Abstract: The cysteine protease caspase-2 has been implicated in the suppression of oncogene-mediated tumor formation. However, the mechanisms underlying the function of caspase-2 as a tumor suppressor are not well defined. In this study, we use a well-characterized mouse lymphoma model and demonstrate a critical role for caspase-2 in maintaining genome stability and in the suppression of tumorigenesis following loss of the essential DNA repair gene ataxia telangiectasia mutated ( Atm ). Our findings suggest that caspase-2 cooperates with ATM to suppress genomic instability, oxidative stress, and tumor progression.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2016
DOI: 10.1038/CDD.2016.81
Publisher: Elsevier BV
Date: 07-2020
Publisher: Informa UK Limited
Date: 12-01-2010
DOI: 10.3109/15376510903559950
Abstract: It is widely accepted that oxidative stress plays a central role in alcohol-induced pathogenesis. Redox-sensitive transcription factors nuclear factor-kappaB (NFkappaB) and activator protein-1 (AP1) are involved in development of alcohol-related diseases. Because of its antioxidative properties, vitamin E is believed to prevent diseases associated with oxidative stress. The aim of the present study was to evaluate the molecular mechanism associated with alcohol-induced oxidative stress and its prevention with vitamin E supplementation. Male Balb/c mice were ided into three groups viz. group I (control), group II (alcohol-treated) and group III (alcohol-treated + Vitamin E supplemented). Group II received 8% alcohol as sole source of drinking fluid while group III was given Vitamin E orally as 5 IU/kg body weight along with 8% alcohol. After 15 days, increases in lipid peroxidation, catalase and GST activity and decreases in SOD activity as well as redox ratio were observed in group II. This was associated with increased apoptosis in this group. Vitamin E supplementation restored the redox status, reduced apoptosis and prevented oxidative stress. Further mRNA expression of cjun, cfos, p65 (NFkappaB) showed increased expression during oxidative stress in group II. Although inhibition in NFkappaB activation was observed with Vitamin E, on the contrary it stimulated AP1 expression. This study supports the fact that alcohol promoted oxidative stress and is the major cause of alcohol toxicity in liver. Vitamin E can mitigate the toxic effects of alcohol and can be suitably used as a potential therapeutic agent for alcohol-induced oxidative damage in liver.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2015
DOI: 10.1038/CDD.2014.216
No related grants have been discovered for Sonia Shalini Shah.