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  1. Article ; Online: Glomerular Biomechanical Stress and Lipid Mediators during Cellular Changes Leading to Chronic Kidney Disease

    Mukut Sharma / Vikas Singh / Ram Sharma / Arnav Koul / Ellen T. McCarthy / Virginia J. Savin / Trupti Joshi / Tarak Srivastava

    Biomedicines, Vol 10, Iss 407, p

    2022  Volume 407

    Abstract: Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental ... ...

    Abstract Hyperfiltration is an important underlying cause of glomerular dysfunction associated with several systemic and intrinsic glomerular conditions leading to chronic kidney disease (CKD). These include obesity, diabetes, hypertension, focal segmental glomerulosclerosis (FSGS), congenital abnormalities and reduced renal mass (low nephron number). Hyperfiltration-associated biomechanical forces directly impact the cell membrane, generating tensile and fluid flow shear stresses in multiple segments of the nephron. Ongoing research suggests these biomechanical forces as the initial mediators of hyperfiltration-induced deterioration of podocyte structure and function leading to their detachment and irreplaceable loss from the glomerular filtration barrier. Membrane lipid-derived polyunsaturated fatty acids (PUFA) and their metabolites are potent transducers of biomechanical stress from the cell surface to intracellular compartments. Omega-6 and ω-3 long-chain PUFA from membrane phospholipids generate many versatile and autacoid oxylipins that modulate pro-inflammatory as well as anti-inflammatory autocrine and paracrine signaling. We advance the idea that lipid signaling molecules, related enzymes, metabolites and receptors are not just mediators of cellular stress but also potential targets for developing novel interventions. With the growing emphasis on lifestyle changes for wellness, dietary fatty acids are potential adjunct-therapeutics to minimize/treat hyperfiltration-induced progressive glomerular damage and CKD.
    Keywords hyperfiltration ; biomechanical forces ; podocytes ; tubules ; omega-6 ; omega-3 ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Permeability factors in nephrotic syndrome and focal segmental glomerulosclerosis

    Virginia J. Savin / Ellen T. McCarthy / Mukut Sharma

    Kidney Research and Clinical Practice, Vol 31, Iss 4, Pp 205-

    2012  Volume 213

    Abstract: Circulating permeability factors have been identified in the plasma of patients with focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria, improvement of proteinuria after treatment with plasmapheresis, and induction of ... ...

    Abstract Circulating permeability factors have been identified in the plasma of patients with focal segmental glomerulosclerosis (FSGS). Post-transplant recurrence of proteinuria, improvement of proteinuria after treatment with plasmapheresis, and induction of proteinuria in experimental animals by plasma fractions each provide evidence for such plasma factors. Advanced proteomic methods have identified candidate molecules in recurrent FSGS. We have proposed cardiotrophin-like cytokine-1 as an active factor in FSGS. Another potential permeability factor in FSGS is soluble urokinase receptor. In our studies, in vitro plasma permeability activity is blocked by substances that may decrease active molecules or block their effects. We have shown that the simple sugar galactose blocks the effect of FSGS serum in vitro and decreases permeability activity when administered to patients. Since the identities of permeability factors and their mechanisms of action are not well defined, treatment of FSGS is empiric. Corticosteroids are the most common agents for initial treatment. Calcineurin inhibitors, such as cyclosporine A, and tacrolimus and immunosuppressive medications, including mycophenylate, induce remission is some patients with steroid-resistant or -dependent nephrotic syndrome. Therapies that diminish proteinuria and slow progression in FSGS as well as other conditions include renin-angiotensin blockade, blood pressure lowering and plasma lipid control. Use of findings from in vitro studies, coupled with definitive identification of pathogenic molecules, may lead to new treatments to arrest FSGS progression and prevent recurrence after transplantation.
    Keywords Cytokines ; Focal glomerulosclerosis ; Galactose ; Kidney transplantation ; Plasmapheresis ; Proteinuria ; Internal medicine ; RC31-1245 ; Specialties of internal medicine ; RC581-951
    Subject code 610
    Language English
    Publishing date 2012-12-01T00:00:00Z
    Publisher The Korean Society of Nephrology
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A mouse model of prenatal exposure to Interleukin-6 to study the developmental origin of health and disease

    Tarak Srivastava / Trupti Joshi / Daniel P. Heruth / Mohammad H. Rezaiekhaligh / Robert E. Garola / Jianping Zhou / Varun C. Boinpelly / Mohammed Farhan Ali / Uri S. Alon / Madhulika Sharma / Gregory B. Vanden Heuvel / Pramod Mahajan / Lakshmi Priya / Yuexu Jiang / Ellen T. McCarthy / Virginia J. Savin / Ram Sharma / Mukut Sharma

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 19

    Abstract: Abstract Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in ... ...

    Abstract Abstract Systemic inflammation in pregnant obese women is associated with 1.5- to 2-fold increase in serum Interleukin-6 (IL-6) and newborns with lower kidney/body weight ratio but the role of IL-6 in increased susceptibility to chronic kidney (CKD) in adult progeny is not known. Since IL-6 crosses the placental barrier, we administered recombinant IL-6 (10 pg/g) to pregnant mice starting at mid-gestation yielded newborns with lower body (p < 0.001) and kidney (p < 0.001) weights. Histomorphometry indicated decreased nephrogenic zone width (p = 0.039) with increased numbers of mature glomeruli (p = 0.002) and pre-tubular aggregates (p = 0.041). Accelerated maturation in IL-6 newborns was suggested by early expression of podocyte-specific protein podocin in glomeruli, increased 5-methyl-cytosine (LC–MS analysis for CpG DNA methylation) and altered expression of certain genes of cell-cycle and apoptosis (RT-qPCR array-analysis). Western blotting showed upregulated pJAK2/pSTAT3. Thus, treating dams with IL-6 as a surrogate provides newborns to study effects of maternal systemic inflammation on future susceptibility to CKD in adulthood.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Transcription Factor β-Catenin Plays a Key Role in Fluid Flow Shear Stress-Mediated Glomerular Injury in Solitary Kidney

    Tarak Srivastava / Daniel P. Heruth / R. Scott Duncan / Mohammad H. Rezaiekhaligh / Robert E. Garola / Lakshmi Priya / Jianping Zhou / Varun C. Boinpelly / Jan Novak / Mohammed Farhan Ali / Trupti Joshi / Uri S. Alon / Yuexu Jiang / Ellen T. McCarthy / Virginia J. Savin / Ram Sharma / Mark L. Johnson / Mukut Sharma

    Cells, Vol 10, Iss 1253, p

    2021  Volume 1253

    Abstract: Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo . FFSS-treated cultured podocytes show upregulated AKT-GSK3β-β-catenin signaling. The present study was undertaken to confirm (i) the activation of β-catenin ... ...

    Abstract Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function in vivo . FFSS-treated cultured podocytes show upregulated AKT-GSK3β-β-catenin signaling. The present study was undertaken to confirm (i) the activation of β-catenin signaling in podocytes in vivo using unilaterally nephrectomized (UNX) TOPGAL mice with the β-galactosidase reporter gene for β-catenin activation, (ii) β-catenin translocation in FFSS-treated mouse podocytes, and (iii) β-catenin signaling using publicly available data from UNX mice. The UNX of TOPGAL mice resulted in glomerular hypertrophy and increased the mesangial matrix consistent with hemodynamic adaptation. Uninephrectomized TOPGAL mice showed an increased β-galactosidase expression at 4 weeks but not at 12 weeks, as assessed using immunofluorescence microscopy ( p < 0.001 at 4 weeks; p = 0.16 at 12 weeks) and X-gal staining ( p = 0.008 at 4 weeks; p = 0.65 at 12 weeks). Immunofluorescence microscopy showed a significant increase in phospho-β-catenin (Ser552, p = 0.005) at 4 weeks but not at 12 weeks ( p = 0.935) following UNX, and the levels of phospho-β-catenin (Ser675) did not change. In vitro FFSS caused a sustained increase in the nuclear translocation of phospho-β-catenin (Ser552) but not phospho-β-catenin (Ser675) in podocytes. The bioinformatic analysis of the GEO dataset, #GSE53996, also identified β-catenin as a key upstream regulator. We conclude that transcription factor β-catenin mediates FFSS-induced podocyte (glomerular) injury in solitary kidney.
    Keywords podocytes ; fluid flow shear stress ; glomerular hemodynamics ; hyperfiltration ; glomerular filtration barrier ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Multiple Targets for Novel Therapy of FSGS Associated with Circulating Permeability Factor

    Virginia J. Savin / Mukut Sharma / Jianping Zhou / David Genochi / Ram Sharma / Tarak Srivastava / Amna Ilaha / Pooja Budhiraja / Aditi Gupta / Ellen T. McCarthy

    BioMed Research International, Vol

    2017  Volume 2017

    Abstract: A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected ... ...

    Abstract A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A or anti-immunoglobulin, or lipopheresis. Oral or intravenous galactose also decreases Palb activity. Studies of glomeruli have shown that several strategies prevent the action of FSGS sera. These include blocking receptor-ligand interactions, modulating cell reactions using indomethacin or eicosanoids 20-HETE or 8,9-EET, and enhancing cytoskeleton and protein interactions using calcineurin inhibitors, glucocorticoids, or rituximab. We have identified cardiotrophin-like cytokine factor 1 (CLCF-1) as a candidate for the permeability factor. Therapies specific to CLCF-1 include potential use of cytokine receptor-like factor (CRLF-1) and inhibition of Janus kinase 2. Combined therapy using multiple modalities offers therapy to reverse proteinuria and prevent scarring.
    Keywords Medicine ; R
    Subject code 306
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Normalization of Testosterone Levels After Testosterone Replacement Therapy Is Not Associated With Reduced Myocardial Infarction in Smokers

    Olurinde A. Oni, MBBS, MPH / Rishi Sharma, MD, MHSA / Guoqing Chen, MD, PhD, MPH / Mukut Sharma, PhD / Kamal Gupta, MD / Buddhadeb Dawn, MD / Ram Sharma, PhD / Deepak Parashara, MD / Virginia J. Savin, MD / George Cherian, MD / John A. Ambrose, MD / Rajat S. Barua, MD, PhD

    Mayo Clinic Proceedings: Innovations, Quality & Outcomes, Vol 1, Iss 1, Pp 57-

    2017  Volume 66

    Abstract: Objective: To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without ... ...

    Abstract Objective: To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without history of MI and stroke. Participants and Methods: Data from 18,055 males with known CS status and low TT levels who received TRT at the Veterans Health Administration between December 1, 1999, and May 31, 2014, were grouped into (1) current smokers with normalized TT, (2) current smokers with nonnormalized TT, (3) nonsmokers with normalized TT, and (4) nonsmokers with nonnormalized TT. Combined effect of CS status and TT level normalization after TRT on all-cause mortality, MI, and stroke was compared using propensity score–weighted Cox proportional hazard models. Results: Normalization of serum TT levels in nonsmokers was associated with a significant decrease in all-cause mortality (hazard ratio [HR]=0.526; 95% CI, 0.477-0.581; P<.001) and MI (HR=0.717; 95% CI, 0.522-0.986; P<.001). Among current smokers, normalization of serum TT levels was associated with a significant decrease in only all-cause mortality (HR=0.563; 95% CI, 0.488-0.649; P<.001) without benefit in MI (HR=1.096; 95% CI, 0.698-1.720; P=.69). Importantly, compared with nonsmokers with normalized TT, all-cause mortality (HR=1.242; 95% CI, 1.104-1.396; P<.001), MI (HR=1.706; 95% CI, 1.242-2.342; P=.001), and stroke (HR=1.590; 95% CI, 1.013-2.495; P=.04) were significantly higher in current smokers with normalized TT. Conclusion: We conclude that active CS may negate the protective effect of testosterone level normalization on all-cause mortality and MI after TRT.
    Keywords Medicine (General) ; R5-920
    Subject code 616
    Language English
    Publishing date 2017-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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