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  • 1
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    Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of the American Society of Nephrology Vol. 31, No. 7 ( 2020-7), p. 1479-1495
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 7 ( 2020-7), p. 1479-1495
    Abstract: Although genetic mutations in α -actinin-4 (ACTN4) are linked with proteinuric glomerulosclerosis in humans, the effect of post-translational modifications is unknown. The authors show that ACTN4—an actin crosslinking cytoskeletal protein—is phosphorylated at serine 159 (S159) in podocytes. Compared with wild-type ACTN4, phosphomimetic ACTN4 protein demonstrated increased binding affinity to F-actin, and phosphomimetic mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress compared with controls. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. These biochemical, cellular, and renal effects are similar to those seen in mutant ACTN4-mediated proteinuric glomerulosclerosis. High extracellular glucose and TGF- β levels stimulate ACTN4 phosphorylation. These findings suggest that, in addition to genetic mutations, increased phosphorylation of ACTN4 may mediate podocyte injury and kidney disease. Background Genetic mutations in α -actinin-4 (ACTN4)—an important actin crosslinking cytoskeletal protein that provides structural support for kidney podocytes—have been linked to proteinuric glomerulosclerosis in humans. However, the effect of post-translational modifications of ACTN4 on podocyte integrity and kidney function is not known. Methods Using mass spectrometry, we found that ACTN4 is phosphorylated at serine (S) 159 in human podocytes. We used phosphomimetic and nonphosphorylatable ACTN4 to comprehensively study the effects of this phosphorylation in vitro and in vivo . We conducted x-ray crystallography, F-actin binding and bundling assays, and immunofluorescence staining to evaluate F-actin alignment. Microfluidic organ-on-a-chip technology was used to assess for detachment of podocytes simultaneously exposed to fluid flow and cyclic strain. We then used CRISPR/Cas9 to generate mouse models and assessed for renal injury by measuring albuminuria and examining kidney histology. We also performed targeted mass spectrometry to determine whether high extracellular glucose or TGF- β levels increase phosphorylation of ACTN4. Results Compared with the wild type ACTN4, phosphomimetic ACTN4 demonstrated increased binding and bundling activity with F-actin in vitro . Phosphomimetic Actn4 mouse podocytes exhibited more spatially correlated F-actin alignment and a higher rate of detachment under mechanical stress. Phosphomimetic Actn4 mice developed proteinuria and glomerulosclerosis after subtotal nephrectomy. Moreover, we found that exposure to high extracellular glucose or TGF- β stimulates phosphorylation of ACTN4 at S159 in podocytes. Conclusions These findings suggest that increased phosphorylation of ACTN4 at S159 leads to biochemical, cellular, and renal pathology that is similar to pathology resulting from human disease–causing mutations in ACTN4. ACTN4 may mediate podocyte injury as a consequence of both genetic mutations and signaling events that modulate phosphorylation.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2019101032
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2029124-3
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  • 2
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    Advancing Nephrology : Division Leaders Advise ASN
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Clinical Journal of the American Society of Nephrology Vol. 16, No. 2 ( 2021-02), p. 319-327
    Details
    In: Clinical Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 16, No. 2 ( 2021-02), p. 319-327
    Abstract: New treatments, new understanding, and new approaches to translational research are transforming the outlook for patients with kidney diseases. A number of new initiatives dedicated to advancing the field of nephrology—from value-based care to prize competitions—will further improve outcomes of patients with kidney disease. Because of individual nephrologists and kidney organizations in the United States, such as the American Society of Nephrology, the National Kidney Foundation, and the Renal Physicians Association, and international nephrologists and organizations, such as the International Society of Nephrology and the European Renal Association–European Dialysis and Transplant Association, we are beginning to gain traction to invigorate nephrology to meet the pandemic of global kidney diseases. Recognizing the timeliness of this opportunity, the American Society of Nephrology convened a Division Chief Retreat in Dallas, Texas, in June 2019 to address five key issues: ( 1 ) asserting the value of nephrology to the health system; ( 2 ) productivity and compensation; ( 3 ) financial support of faculty’s and divisions’ educational efforts; ( 4 ) faculty recruitment, retention, diversity, and inclusion; and ( 5 ) ensuring that fellowship programs prepare trainees to provide high-value nephrology care and enhance attraction of trainees to nephrology. Herein, we highlight the outcomes of these discussions and recommendations to the American Society of Nephrology.
    Type of Medium: Online Resource
    ISSN: 1555-9041 , 1555-905X
    URL: Article
    DOI: 10.2215/CJN.01550220
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2216582-4
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  • 3
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    Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice
    American Society for Clinical Investigation ; 2006
    In:  Journal of Clinical Investigation Vol. 116, No. 8 ( 2006-8-1), p. 2218-2225
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 116, No. 8 ( 2006-8-1), p. 2218-2225
    Type of Medium: Online Resource
    ISSN: 0021-9738
    URL: Article
    DOI: 10.1172/JCI16980
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2006
    detail.hit.zdb_id: 2018375-6
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  • 4
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    Abstract 14: Caskin2 is a Novel Regulator of Endothelial Cell Quiescence
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 34, No. suppl_1 ( 2014-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. suppl_1 ( 2014-05)
    Abstract: Maintenance of vascular homeostasis is an active process that is dependent on continuous signaling by the quiescent endothelial cells (ECs) that line mature vessels. The signaling pathways that are active in quiescent ECs are distinct from those that regulate angiogenesis but are comparatively poorly understood. Here we demonstrate that the previously uncharacterized scaffolding protein Caskin2 is a novel regulator of EC quiescence. Caskin2 is highly expressed in ECs from various vascular beds both in vitro and in vivo. Morpholino knockdown of Caskin2 in zebrafish results in abnormal vascular development characterized by overly branched intersegmental vessels and failure to form the dorsal longitudinal vessels. Interestingly, Caskin2 knockout mice are viable and fertile. However, compared to wild-type mice, adult Caskin2 knockout mice have significantly more abdominal adipose and higher fasting blood glucose levels even when fed a standard chow diet. In vitro, Caskin2 overexpression inhibits serum-induced EC proliferation and DNA synthesis but promotes EC survival during serum starvation. Caskin2 localizes to the nucleus as well as the cytoplasm and promotes the downregulation of genes associated with EC activation (e.g., IL-8, VEGFR2, ANG2) and the upregulation of genes associated with EC quiescence (e.g., Notch1, KLF2/4, ANG1). More broadly, pathway analysis of microarray data demonstrates that Caskin2 primarily regulates cell cycle and metabolic genes. Additional data suggest that these effects result from the interaction of Caskin2 with the Ser/Thr phosphatase PP1alpha, which is mediated by a consensus PP1 binding motif at the Caskin2 N-terminus. Taken together, our data demonstrate that Caskin2 is sufficient to suppress EC proliferation in vitro and necessary to prevent dysregulated angiogenesis in at least one in vivo model. These findings indicate that Caskin2 is a novel regulator of EC quiescence and suggest a role for Caskin2 in the prevention of EC dysfunction in vivo. Understanding Caskin2’s function on the molecular level may lead to the development of novel pharmacological approaches to prevent inappropriate angiogenesis, normalize dysfunctional vessels, and improve vascular function in a variety of cardiovascular diseases.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.34.suppl_1.14
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1494427-3
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  • 5
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    Competing Actions of Type 1 Angiotensin II Receptors Expressed on T Lymphocytes and Kidney Epithelium during Cisplatin-Induced AKI
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of the American Society of Nephrology Vol. 27, No. 8 ( 2016-8), p. 2257-2264
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 27, No. 8 ( 2016-8), p. 2257-2264
    Abstract: Inappropriate activation of the renin-angiotensin system (RAS) contributes to many CKDs. However, the role of the RAS in modulating AKI requires elucidation, particularly because stimulating type 1 angiotensin II (AT 1 ) receptors in the kidney or circulating inflammatory cells can have opposing effects on the generation of inflammatory mediators that underpin the pathogenesis of AKI. For example, TNF- α is a fundamental driver of cisplatin nephrotoxicity, and generation of TNF- α is suppressed or enhanced by AT 1 receptor signaling in T lymphocytes or the distal nephron, respectively. In this study, cell tracking experiments with CD4-Cre mT/mG reporter mice revealed robust infiltration of T lymphocytes into the kidney after cisplatin injection. Notably, knockout of AT 1 receptors on T lymphocytes exacerbated the severity of cisplatin-induced AKI and enhanced the cisplatin-induced increase in TNF- α levels locally within the kidney and in the systemic circulation. In contrast, knockout of AT 1 receptors on kidney epithelial cells ameliorated the severity of AKI and suppressed local and systemic TNF- α production induced by cisplatin. Finally, disrupting TNF- α production specifically within the renal tubular epithelium attenuated the AKI and the increase in circulating TNF- α levels induced by cisplatin. These results illustrate discrepant tissue–specific effects of RAS stimulation on cisplatin nephrotoxicity and raise the concern that inflammatory mediators produced by renal parenchymal cells may influence the function of remote organs by altering systemic cytokine levels. Our findings suggest selective inhibition of AT 1 receptors within the nephron as a promising intervention for protecting patients from cisplatin-induced nephrotoxicity.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.2015060683
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2029124-3
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  • 6
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    Angiotensin-Converting Enzyme 2 Deficiency Is Associated With Impaired Gestational Weight Gain and Fetal Growth Restriction
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Hypertension Vol. 58, No. 5 ( 2011-11), p. 852-858
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 58, No. 5 ( 2011-11), p. 852-858
    Abstract: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system that influences the relative expression of angiotensin II (Ang II) and Ang-(1-7). Although ACE2 expression increases in normal pregnancy, the impact of ACE2 deficiency in pregnancy has not been elucidated. We determined the influence of ACE2 deficiency on circulating and tissue renin-angiotensin system components, fetal and maternal growth characteristics, and maternal hemodynamics (mean blood pressure and cardiac output) at day 18 of gestation. Gestational body weight gain was lower in the ACE2 knockout (KO) versus C57BL/6 (wild-type) mice (30.3±4.7 versus 38.2±1.0 g; P 〈 0.001). Fetal weight (0.94±0.1 versus 1.24±0.01 g; P 〈 0.01) and length (19.6±0.2 versus 22.2±0.2 mm; P 〈 0.001) were less in KO. Mean blood pressure was significantly reduced in C57BL/6 with pregnancy; it was elevated ( P 〈 0.05) in the KO virgin and pregnant mice, and this was associated with an increased cardiac output in both C57BL/6 and KO pregnant mice ( P 〈 0.05). Plasma Ang-(1-7) was reduced in pregnant KO mice ( P 〈 0.05). Placenta Ang II levels were higher in KO mice (52.9±6.0 versus 22.0±3.3 fmol/mg of protein; P 〈 0.001). Renal Ang II levels were greater in KO virgin mice (30.0±1.7 versus 23.7±1.1 fmol/mg of protein; P 〈 0.001). There was no change in the Ang-(1-7) levels in the KO placenta and virgin kidney. These results suggest that ACE2 deficiency and associated elevated placenta Ang II levels impact pregnancy by impairing gestational weight gain and restricting fetal growth.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.111.179358
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 2094210-2
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  • 7
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    Targeting eNOS in Pancreatic Cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 17 ( 2012-09-01), p. 4472-4482
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 17 ( 2012-09-01), p. 4472-4482
    Abstract: Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS, NOS3, or NOS III) has been implicated recently in the pathogenesis of PDACs. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDACs. Genetic deficiency in eNOS limited the development of preinvasive pancreatic lesions and trended toward an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor NG-nitro-L-arginine methyl ester (l-NAME). Similarly, other transgenic models of oncogenic KRas–driven tumors responded to l-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which l-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose l-NAME for clinical investigations in treatment of PDACs and possibly other KRas-driven human cancers. Cancer Res; 72(17); 4472–82. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-12-0057
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Increased phosphorylation of ACTN4 leads to podocyte vulnerability and proteinuric kidney disease and is stimulated by high glucose and TGF‐b
    Wiley ; 2020
    In:  The FASEB Journal Vol. 34, No. S1 ( 2020-04), p. 1-1
    Details
    In: The FASEB Journal, Wiley, Vol. 34, No. S1 ( 2020-04), p. 1-1
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v34.S1
    DOI: 10.1096/fasebj.2020.34.s1.02190
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 9
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    Abstract 066: The Undescribed Protein Caskin2 Is a Novel Regulator of eNOS Phosphorylation and Systemic Blood Pressure
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Hypertension Vol. 66, No. suppl_1 ( 2015-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. suppl_1 ( 2015-09)
    Abstract: Disruptions in the function of the quiescent endothelial cells (ECs) that line mature vessels can both result in and contribute to the progression of numerous cardiovascular diseases including hypertension, atherosclerosis, and disorders of vascular permeability. Despite recent attention, the signaling pathways that are active in quiescent ECs remain poorly characterized relative to those that regulate EC activation. In an effort to provide mechanistic insight into these pathways, we have characterized the previously undescribed protein Caskin2, which we hypothesize is a novel regulator of EC quiescence. Caskin2 is expressed in ECs throughout the vasculature, including the aorta, coronary arteries, and renal glomeruli. In vitro, Caskin2 promotes a quiescent EC phenotype characterized by decreased proliferation and increased resistance to apoptosis-inducing factors. Caskin2 knockout mice are viable and fertile. However, preliminary radiotelemetry measurements indicate that Caskin2 knockout (KO) mice have mildly elevated systemic blood pressure (BP). Compared to wild type (WT) littermates (n=8), Caskin2 KO mice (n=7) had increased mean arterial pressure (119+/-1 vs. 113+/-1, p=0.012), systolic BP (138+/-2 vs. 132+/-2, p=0.023), and diastolic BP (99+/-1 vs. 93+/-1, p=0.014) at baseline. To explore the molecular mechanisms of Caskin2’s effects, we used mass spectrometry to identify interacting proteins. Among the 67 proteins identified were the Ser/Thr phosphatase protein phosphatase 1 (PP1) and eNOS. Using standard in vitro biochemical techniques, we demonstrated that Caskin2 acts as a PP1 regulatory subunit. Interestingly, homologous expression of Caskin2 in vitro resulted in a marked increase in phosphorylation of eNOS on S1177, which is known to promote eNOS activity, and a decrease in phosphorylation on T495, which is associated with eNOS inhibition. Finally, PP1 has been shown to dephosphorylate eNOS T495 in vitro, suggesting a molecular mechanism for our in vivo findings. Ongoing work aims to determine if the interaction of Caskin2 and PP1 is required for the Caskin2-induced increase in activating phosphorylation of eNOS and to characterize the physiological mechanisms responsible for Caskin2’s effects on BP in more detail.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.66.suppl_1.066
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 2094210-2
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  • 10
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    Abstract 602: Mass Spectrometry Based Characterization of Angiotensin Metabolism in ACE2 Deficient Mice Treated with RAS Blockers
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Hypertension Vol. 62, No. suppl_1 ( 2013-09)
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 62, No. suppl_1 ( 2013-09)
    Abstract: The Renin-Angiotensin-System is a peptide hormone cascade being responsible for the regulation of blood pressure and fluid balance through a sophisticated signaling network. During recent years the local Renin-Angiotensin-System (RAS) moved increasingly into the focus of research as the expression of multiple angiotensin processing enzymes had been reported for tissues. Nevertheless, scientific progress in this field is hampered due to the obvious presence of technical caveats in the analysis of the local RAS, which are indicated by a tremendous variation of tissue angiotensin levels reported in the literature. Hence, in order to assess the functions of the local RAS in different tissues, a solid and reproducible assay for the measurement of endogenous angiotensin peptide levels in tissues would be essential. We developed a novel mass-spectrometry-based method allowing the quantification of up to 10 angiotensin metabolites in tissue samples simultaneously. This novel tool was tested for applicability in murine studies by measuring tissue and plasma levels of angiotensin metabolites in wildtype and ACE2 knockout mice treated with various RAS-interfering drugs. The study provided deep insights into the systemic and tissue specific RAS revealing drug specific responses. As expected, the knockout of ACE2 resulted in increased Angiotensin II levels in hearts of knockout animals while the kidneys were only moderately affected. Enalapril treatment significantly lowered Angiotensin II levels in all investigated tissues. Surprising tissue specific effects were observed regarding other angiotensin metabolites, which underlines the importance of the comprehensive analysis of the RAS for conclusive interpretation of pharmacologic studies and allows to draw conclusions about expression levels of RAS-enzymes in the tissue of interest. Mass spectrometry based multiplex quantification of tissue angiotensin peptides (Tissue RAS-Fingerprinting) is a potent analytic tool for applications in basic science and drug development. Multiplex analysis of the tissue RAS provides new insights that might lead to the development of novel drugs and therapeutic concepts for the treatment of cardiovascular diseases in the future.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/hyp.62.suppl_1.A602
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 2094210-2
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