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

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

    Biomedicines

    2022  Volume 10, Issue 2

    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.
    Language English
    Publishing date 2022-02-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines10020407
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. 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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  3. Article ; Online: Galactose treatment in focal segmental glomerulosclerosis.

    Trachtman, Howard / Savin, Virginia J

    Pediatric nephrology (Berlin, Germany)

    2013  Volume 29, Issue 5, Page(s) 931

    MeSH term(s) Female ; Galactose/therapeutic use ; Humans ; Kidney Glomerulus/drug effects ; Male ; Nephrotic Syndrome/congenital ; Proteinuria/drug therapy
    Chemical Substances Galactose (X2RN3Q8DNE)
    Language English
    Publishing date 2013-12-22
    Publishing country Germany
    Document type Letter ; Comment
    ZDB-ID 631932-4
    ISSN 1432-198X ; 0931-041X
    ISSN (online) 1432-198X
    ISSN 0931-041X
    DOI 10.1007/s00467-013-2700-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Prostanoid receptors in hyperfiltration-mediated glomerular injury: Novel agonists and antagonists reveal opposing roles for EP2 and EP4 receptors.

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

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology

    2022  Volume 36, Issue 10, Page(s) e22559

    Abstract: Increased fluid-flow shear stress (FFSS) contributes to hyperfiltration-induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 ( ... ...

    Abstract Increased fluid-flow shear stress (FFSS) contributes to hyperfiltration-induced podocyte and glomerular injury resulting in progression of chronic kidney disease (CKD). We reported that increased FFSS in vitro and in vivo upregulates PGE2 receptor EP2 (but not EP4 expression), COX2-PGE
    MeSH term(s) Albumins ; Albuminuria ; Animals ; Creatinine ; Cyclooxygenase 2 ; Dinoprostone/metabolism ; Glycogen Synthase Kinase 3 beta ; Gonadal Steroid Hormones ; Mice ; Proto-Oncogene Proteins c-akt ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Receptors, Prostaglandin E, EP4 Subtype ; Renal Insufficiency, Chronic ; beta Catenin
    Chemical Substances Albumins ; Gonadal Steroid Hormones ; Receptors, Prostaglandin E, EP2 Subtype ; Receptors, Prostaglandin E, EP4 Subtype ; beta Catenin ; Creatinine (AYI8EX34EU) ; Cyclooxygenase 2 (EC 1.14.99.1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2022-09-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 639186-2
    ISSN 1530-6860 ; 0892-6638
    ISSN (online) 1530-6860
    ISSN 0892-6638
    DOI 10.1096/fj.202200875R
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids.

    Sharma, Mukut / Sharma, Ram / McCarthy, Ellen T / Savin, Virginia J / Srivastava, Tarak

    Prostaglandins & other lipid mediators

    2017  Volume 132, Page(s) 59–68

    Abstract: Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in ... ...

    Abstract Hyperfiltration is a well-known risk factor in progressive loss of renal function in chronic kidney disease (CKD) secondary to various diseases. A reduced number of functional nephrons due to congenital or acquired cause(s) results in hyperfiltration in the remnant kidney. Hyperfiltration-associated increase in biomechanical forces, namely pressure-induced tensile stress and fluid flow-induced shear stress (FFSS) determine cellular injury and response. We believe the current treatment of CKD yields limited success because it largely attenuates pressure-induced tensile stress changes but not the effect of FFSS on podocytes. Studies on glomerular podocytes, tubular epithelial cells and bone osteocytes provide evidence for a significant role of COX-2 generated PGE
    MeSH term(s) Animals ; Biomechanical Phenomena ; Dinoprostone/metabolism ; Eicosanoids/metabolism ; Humans ; Kidney Glomerulus/cytology ; Kidney Glomerulus/injuries ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/physiology ; Mechanical Phenomena ; Podocytes/metabolism
    Chemical Substances Eicosanoids ; Dinoprostone (K7Q1JQR04M)
    Language English
    Publishing date 2017-01-17
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1426962-4
    ISSN 2212-196X ; 1098-8823 ; 0090-6980
    ISSN (online) 2212-196X
    ISSN 1098-8823 ; 0090-6980
    DOI 10.1016/j.prostaglandins.2017.01.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Plasma "factors" in recurrent nephrotic syndrome after kidney transplantation: causes or consequences of glomerular injury?

    Savin, Virginia J / Sharma, Mukut

    American journal of kidney diseases : the official journal of the National Kidney Foundation

    2009  Volume 54, Issue 3, Page(s) 406–409

    MeSH term(s) Humans ; Interleukin-1 Receptor-Like 1 Protein ; Intracellular Signaling Peptides and Proteins/blood ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Kidney Transplantation/adverse effects ; Membrane Proteins/blood ; Nephrotic Syndrome/blood ; Nephrotic Syndrome/surgery ; Receptors, Cell Surface/blood ; Recurrence
    Chemical Substances IL1RL1 protein, human ; Interleukin-1 Receptor-Like 1 Protein ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; NPHS2 protein ; Receptors, Cell Surface
    Language English
    Publishing date 2009-09
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 604539-x
    ISSN 1523-6838 ; 0272-6386
    ISSN (online) 1523-6838
    ISSN 0272-6386
    DOI 10.1053/j.ajkd.2009.06.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Hyperfiltration-mediated Injury in the Remaining Kidney of a Transplant Donor.

    Srivastava, Tarak / Hariharan, Sundaram / Alon, Uri S / McCarthy, Ellen T / Sharma, Ram / El-Meanawy, Ashraf / Savin, Virginia J / Sharma, Mukut

    Transplantation

    2018  Volume 102, Issue 10, Page(s) 1624–1635

    Abstract: Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been ... ...

    Abstract Kidney donors face a small but definite risk of end-stage renal disease 15 to 30 years postdonation. The development of proteinuria, hypertension with gradual decrease in kidney function in the donor after surgical resection of 1 kidney, has been attributed to hyperfiltration. Genetic variations, physiological adaptations, and comorbidities exacerbate the hyperfiltration-induced loss of kidney function in the years after donation. A focus on glomerular hemodynamics and capillary pressure has led to the development of drugs that target the renin-angiotensin-aldosterone system (RAAS), but these agents yield mixed results in transplant recipients and donors. Recent work on glomerular biomechanical forces highlights the differential effects of tensile stress and fluid flow shear stress (FFSS) from hyperfiltration. Capillary wall stretch due to glomerular capillary pressure increases tensile stress on podocyte foot processes that cover the capillary. In parallel, increased flow of the ultrafiltrate due to single-nephron glomerular filtration rate elevates FFSS on the podocyte cell body. Although tensile stress invokes the RAAS, FFSS predominantly activates the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis. Distinguishing these 2 mechanisms is critical, as current therapeutic approaches focus on the RAAS system. A better understanding of the biomechanical forces can lead to novel therapeutic agents to target FFSS through the cyclooxygenase 2-prostaglandin E2-EP2 receptor axis in hyperfiltration-mediated injury. We present an overview of several aspects of the risk to transplant donors and discuss the relevance of FFSS in podocyte injury, loss of glomerular barrier function leading to albuminuria and gradual loss of renal function, and potential therapeutic strategies to mitigate hyperfiltration-mediated injury to the remaining kidney.
    MeSH term(s) Age Factors ; Aging/physiology ; Albuminuria/epidemiology ; Albuminuria/etiology ; Albuminuria/physiopathology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Cyclooxygenase 2 Inhibitors/therapeutic use ; Disease Progression ; Glomerular Filtration Rate ; Humans ; Hypertension/epidemiology ; Hypertension/etiology ; Hypertension/physiopathology ; Kidney Failure, Chronic/epidemiology ; Kidney Failure, Chronic/etiology ; Kidney Failure, Chronic/physiopathology ; Kidney Failure, Chronic/prevention & control ; Kidney Glomerulus/pathology ; Kidney Glomerulus/physiopathology ; Living Donors ; Nephrectomy/adverse effects ; Renin-Angiotensin System/drug effects ; Renin-Angiotensin System/physiology ; Stress, Mechanical ; Tissue and Organ Procurement
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Cyclooxygenase 2 Inhibitors
    Language English
    Publishing date 2018-05-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/TP.0000000000002304
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Permeability factors in nephrotic syndrome and focal segmental glomerulosclerosis.

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

    Kidney research and clinical practice

    2012  Volume 31, Issue 4, Page(s) 205–213

    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.
    Language English
    Publishing date 2012-10-16
    Publishing country Korea (South)
    Document type Journal Article ; Review
    ZDB-ID 2656420-8
    ISSN 2211-9132
    ISSN 2211-9132
    DOI 10.1016/j.krcp.2012.10.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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

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

    Cells

    2021  Volume 10, Issue 5

    Abstract: Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte ... ...

    Abstract Increased fluid flow shear stress (FFSS) in solitary kidney alters podocyte function
    MeSH term(s) Animals ; Cell Line ; Databases, Genetic ; Disease Models, Animal ; Genes, fos ; Glomerular Filtration Rate ; Lac Operon ; Lymphoid Enhancer-Binding Factor 1/genetics ; Mechanotransduction, Cellular ; Mice, Transgenic ; Podocytes/metabolism ; Podocytes/pathology ; Promoter Regions, Genetic ; Solitary Kidney/genetics ; Solitary Kidney/metabolism ; Solitary Kidney/pathology ; Solitary Kidney/physiopathology ; Stress, Mechanical ; Transcription Factor 3/genetics ; beta Catenin/genetics ; beta Catenin/metabolism
    Chemical Substances CTNNB1 protein, mouse ; Lymphoid Enhancer-Binding Factor 1 ; Transcription Factor 3 ; beta Catenin
    Language English
    Publishing date 2021-05-19
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells10051253
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Upregulated proteoglycan-related signaling pathways in fluid flow shear stress-treated podocytes.

    Srivastava, Tarak / Joshi, Trupti / Jiang, Yuexu / Heruth, Daniel P / Rezaiekhaligh, Mohamed H / Novak, Jan / Staggs, Vincent S / Alon, Uri S / Garola, Robert E / El-Meanawy, Ashraf / McCarthy, Ellen T / Zhou, Jianping / Boinpelly, Varun C / Sharma, Ram / Savin, Virginia J / Sharma, Mukut

    American journal of physiology. Renal physiology

    2020  Volume 319, Issue 2, Page(s) F312–F322

    Abstract: The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced ... ...

    Abstract The ultrafiltrate flow over the major processes and cell body generates fluid flow shear stress (FFSS) on podocytes. Hyperfiltration-associated increase in FFSS can lead to podocyte injury and detachment. Previously, we showed that FFSS-induced upregulation of the cyclooxygenase 2 (COX2)-PGE
    MeSH term(s) Cyclooxygenase 2/metabolism ; Kidney Glomerulus/metabolism ; Mechanotransduction, Cellular/physiology ; Podocytes/metabolism ; Proteoglycans/metabolism ; Receptors, Prostaglandin E, EP2 Subtype/metabolism ; Stress, Mechanical ; TOR Serine-Threonine Kinases/metabolism ; Transcriptional Activation/physiology ; Up-Regulation
    Chemical Substances Proteoglycans ; Receptors, Prostaglandin E, EP2 Subtype ; Cyclooxygenase 2 (EC 1.14.99.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2020-07-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 603837-2
    ISSN 1522-1466 ; 0363-6127
    ISSN (online) 1522-1466
    ISSN 0363-6127
    DOI 10.1152/ajprenal.00183.2020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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