Perturbations in mitochondrial dynamics by p66Shc lead to renal tubular oxidative injury in human diabetic nephropathy
In this study, we observed changes in mitochondrial morphology and expression of associated proteins in tubules of patients with DN. We demonstrated mitochondrial fragmentation as an important pathogenic feature of tubular cell injury that is linked to oxidative stress and p66Shc up-regulation. In renal proximal tubular cells, alterations in mitochondrial dynamics and expression of fission-fusion proteins were observed under high glucose (HG) ambience, along with p66Shc Ser36 phosphorylation. Gene ablation of p66Shc alleviated HG-induced mitochondrial fragmentation, down-regulated Fis1 and reduced p66Shc-Fis1 binding, incr...
Source: Clinical Science - May 14, 2018 Category: Biomedical Science Authors: Zhan, M., Usman, I., Yu, J., Ruan, L., Bian, X., Yang, J., Yang, S., Sun, L., Kanwar, Y. S. Tags: PublishAheadOfPrint Source Type: research
Hyperfiltration in Ubiquitin C-Terminal Hydrolase L1-Deleted Mice
Neuronal ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that maintains intracellular ubiquitin pools and promotes axonal transport. Uchl1 deletion in mice leads to progressive axonal degeneration, affecting the dorsal root ganglion that harbours axons emanating to the kidney. Innervation is a crucial regulator of renal hemodynamics, though the contribution of neuronal UCHL1 to this is unclear. Immunofluorescence revealed significant neuronal UCHL1 expression in mouse kidney, including periglomerular axons. Glomerular filtration rate trended higher in 6-week-old Uchl1 -/- mice, and by twelve weeks...
Source: Clinical Science - May 8, 2018 Category: Biomedical Science Authors: Boisvert, N. C., Holterman, C. E., Thibodeau, J.-F., Nasrallah, R., Kamto, E., Comin, C. H., da F. Costa, L., Carter, A., Hebert, R. L., Gutsol, A., Cron, G. O., Lacoste, B., Gray, D. A., Kennedy, C. R. Tags: PublishAheadOfPrint Source Type: research
PCSK9 inhibition with alirocumab reduces lipoprotein (a) levels in non-human primates by lowering apolipoprotein (a) production rate.
Therapeutic antibodies targeting PCSK9 (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six non-human primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood sampl...
Source: Clinical Science - May 3, 2018 Category: Biomedical Science Authors: Croyal, M., Tran, T.-T.-T., Blanchard, R. H., Lebail, J.-C., Villard, E. F., Poirier, B., Aguesse, A., Billon-Crossouard, S., Ramin-Mangata, S., Blanchard, V., Nativel, B., Chemello, K., Khantalin, I., Thedrez, A., Janiak, P., Krempf, M., Boixel, C., Lamb Tags: PublishAheadOfPrint Source Type: research
Gremlin activates the Notch pathway linked to renal inflammation
In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-kB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases. (Source: Clinical Science)
Source: Clinical Science - May 2, 2018 Category: Biomedical Science Authors: Lavoz, C., Poveda, J., Marquez-Exposito, L., Rayego-Mateos, S., Rodrigues-Diez, R. R., Ortiz, A., Egido, J., Mezzano, S., Ruiz-Ortega, M. Tags: PublishAheadOfPrint Source Type: research
Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-{beta}
Conclusions -The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β. (Source: Clinical Science)
Source: Clinical Science - April 25, 2018 Category: Biomedical Science Authors: Zhang, C., Qin, J.-J., Gong, F.-H., Tong, J.-J., Cheng, W.-L., Wang, H., Zhang, Y., Zhu, X., She, Z.-G., Xia, H., Zhu, L.-H. Tags: PublishAheadOfPrint Source Type: research
Angiotensin-(1-7) reduces cardiac effects of thyroid hormone by GSK3B/NFATc3 signaling pathway
Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the Renin Angiotensin System (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1-7)) has previously been shown to counterbalance pathological effects of Angiotensin II (Ang II). The aim of this study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpress an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG an...
Source: Clinical Science - April 23, 2018 Category: Biomedical Science Authors: Senger, N., Melo, M. B., Diniz, G. P., Campagnole-Santos, M. J., Souza dos Santos, R. A., Barreto-Chaves, M. L. M. Tags: PublishAheadOfPrint Source Type: research
Galectin-3 downregulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: a new pathway to induce cardiac damage?
Galectin-3 (Gal-3) is increased in heart failure (HF) and promotes cardiac fibrosis and inflammation. We investigated whether Gal-3 modulates oxidative stress in human cardiac fibroblasts, in experimental animal models and in human aortic stenosis (AS). Using proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated the anti-oxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. In parallel, Gal-3 increased peroxide, nitrotyrosine, malondialdehyde and N-carboxymethyl-lysine levels and decreased total antioxidant capacity. Gal-3 decreased prohibitin-2 expression without modifying other mitocho...
Source: Clinical Science - April 19, 2018 Category: Biomedical Science Authors: Ibarrola, J., Arrieta, V., Sadaba, R., Martinez-Martinez, E., Garcia-Pena, A., Alvarez, V., Fernandez-Celis, A., Gainza, A., Santamaria, E., Fernandez-Irigoyen, J., Cachofeiro, V., Zalba, G., Fay, R., Rossignol, P., Lopez-Andres, N. Tags: PublishAheadOfPrint Source Type: research
Sodium bicarbonate loading limits tubular cast formation independent of glomerular injury and proteinuria in dahl salt-sensitive rats
Sodium bicarbonate (NaHCO3) slows the decline in kidney function in patients with chronic kidney disease (CKD), yet the mechanisms mediating this effect remain unclear. The Dahl salt-sensitive (SS) rat develops hypertension and progressive renal injury when fed a high salt diet; however, the effect of alkali loading on kidney injury has never been investigated in this model. We hypothesized that 'NaHCO3 protects from the development of renal injury in Dahl salt-sensitive rats via luminal alkalization which limits the formation of tubular casts, which are a prominent pathological feature in this model. To examine this hypot...
Source: Clinical Science - April 12, 2018 Category: Biomedical Science Authors: Ray, S. C., Patel, B., Irsik, D. L., Sun, J., Ocasio, H., Crislip, G. R., Jin, C. H., Chen, J. K., Baban, B., Polichnowski, A. J., O'Connor, P. M. Tags: PublishAheadOfPrint Source Type: research
Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease.
Conclusion: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short and long-term effect of dietary salt in SVD. (Source: Clinical Science)
Source: Clinical Science - April 9, 2018 Category: Biomedical Science Authors: Bailey, E. L., McBride, M. W., McClure, J. D., Beattie, W., Graham, D., Dominiczak, A. F., Smith, C., Wardlaw, J. M. Tags: PublishAheadOfPrint Source Type: research
Impaired endocrine-metabolic homeostasis: underlying mechanism of its induction by unbalanced diet
Conclusions : OS may be actively involved in the mechanism by which unbalanced/unhealthy diets induce β-cell dysfunction. Since metabolic-endocrine dysfunctions recorded in HS rats resembled those measured in human pre-diabetes, knowledge of its molecular mechanism could help to develop appropriate strategies to prevent the progression of this metabolic state towards Type 2 Diabetes. (Source: Clinical Science)
Source: Clinical Science - April 6, 2018 Category: Biomedical Science Authors: Maiztegui, B., Roman, C. L., Gagliardino, J. J., Flores, L. E. Tags: PublishAheadOfPrint Source Type: research
Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) Protects against Cisplatin-induced Acute Kidney Injury
Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active small-molecule HIF PHD inhibitor for the treatment of anemia in patients with CKD. The current study a...
Source: Clinical Science - March 26, 2018 Category: Biomedical Science Authors: Yang, Y., Yu, X., Zhang, Y., Ding, G., Zhu, C., Huang, S., Jia, Z., Zhang, A. Tags: PublishAheadOfPrint Source Type: research
Cardiotrophin-1 attenuates experimental colitis in mice
In this study the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knock-out and wild type mice by administration of dextran sodium sulphate (DSS) in the drinking water during 7 days. CT-1 knock-out mice showed higher colon damage and disease severity than wild type mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) were administered during 3 days to wild type, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (TNF-α, INF, IL-17, IL-10, iNOS), colon da...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Prieto-Vicente, V., Sanchez-Garrido, A. I., Blanco-Gozalo, V., Arevalo, M., Garcia-Sanchez, E. M., Lopez-Montanes, D., Quiros, Y., Lopez-Hernandez, F. J., Rodriguez-Perez, A., Lopez-Novoa, J. M. Tags: PublishAheadOfPrint Source Type: research
MicroRNA-27-3p regulates TLR2/4-dependent mouse alveolar macrophage activation by targeting PPAR{gamma}
Activation of alveolar macrophages (AMs) and the release of cytokines play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the mechanisms of AM activation. miRNAs have recently emerged as key regulators of inflammation and as mediators of macrophage activation and polarization. We identified potential miRNAs related to AM activation using miRNA microarray analysis, which showed that miR-27-3p expression was up-regulated in AMs&nb...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Wang, D., He, S., Liu, B., Liu, C. Tags: PublishAheadOfPrint Source Type: research
CTRP3 attenuates high-fat diet-induced male reproductive dysfunction in mice
Recent studies have suggested a role for abdominal obesity in male infertility. Previous studies have found that cell apoptosis exerts an important role in obesity-related male infertility. C1q/TNF-related protein 3 (CTRP3), a paralog of adiponectin, has been proposed to exert anti-apoptotic effects and to attenuate diabetes-related cardiac injuries. However, the role of CTRP3 in high-fat diet (HFD)-induced spermatogenic impairment remains unclear. In the present study, we fed male mice a HFD for 24 weeks to induce obesity. The expression of CTRP3 was decreased by HFD feeding. Supplementation with the recombinant human glo...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Mu, Y., Yin, T.-l., Yin, L., Hu, X., Yang, J. Tags: PublishAheadOfPrint Source Type: research
Identification of protein phosphatase involvement in the AT2-receptor induced activation of endothelial nitric oxide synthase
The angiotensin AT2 receptor (AT2R) promotes vasodilation by nitric oxide (NO) release from endothelial cells. However, the mechanisms underlying the AT2R-induced stimulation of endothelial NO synthase (eNOS) is still not completely understood. Therefore, we investigated whether in addition to the known AT2R-mediated phosphorylation of eNOS at Ser1177, activation of phosphatases and dephosphorylation of eNOS at Tyr657 and Thr495 are also involved. Human Aortic Endothelial Cells (HAEC) were stimulated with the AT2R-agonist C21 (1µM) in the presence or absence of either PD123319 (10µM; AT2R-antagonist), L-NAME (1...
Source: Clinical Science - March 14, 2018 Category: Biomedical Science Authors: Peluso, A. A., Bertelsen, J. B., Andersen, K., Mortensen, T. P., Hansen, P. B., Sumners, C., Bader, M., Santos, R. A., Steckelings, U. M. Tags: PublishAheadOfPrint Source Type: research
