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• W2802384383 abstract "Proteinuria encompasses diverse causes including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely depends on the podocyte: a terminally differentiated epithelial cell type covering the outer surface of the glomerulus. Compromised podocyte structure is one of the earliest signs of glomerular injury. The phenotype of diverse animal models and podocyte cell culture firmly established the essential role of the actin cytoskeleton in maintaining functional podocyte structure. Podocyte foot processes, actin-based membrane extensions, contain 2 molecularly distinct “hubs” that control actin dynamics: a slit diaphragm and focal adhesions. Although loss of foot processes encompasses disassembly of slit diaphragm multiprotein complexes, as long as cells are attached to the glomerular basement membrane, focal adhesions will be the sites in which stress due to filtration flow is counteracted by forces generated by the actin network in foot processes. Numerous studies within last 20 years have identified actin binding and regulatory proteins as well as integrins as essential components of signaling and actin dynamics at focal adhesions in podocytes, suggesting that some of them may become novel, druggable targets for proteinuric kidney diseases. Here we review evidence supporting the idea that current treatments for chronic kidney diseases beneficially and directly target the podocyte actin cytoskeleton associated with focal adhesions and suggest that therapeutic reagents that target the focal adhesion-regulated actin cytoskeleton in foot processes have potential to modernize treatments for chronic kidney diseases. Proteinuria encompasses diverse causes including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely depends on the podocyte: a terminally differentiated epithelial cell type covering the outer surface of the glomerulus. Compromised podocyte structure is one of the earliest signs of glomerular injury. The phenotype of diverse animal models and podocyte cell culture firmly established the essential role of the actin cytoskeleton in maintaining functional podocyte structure. Podocyte foot processes, actin-based membrane extensions, contain 2 molecularly distinct “hubs” that control actin dynamics: a slit diaphragm and focal adhesions. Although loss of foot processes encompasses disassembly of slit diaphragm multiprotein complexes, as long as cells are attached to the glomerular basement membrane, focal adhesions will be the sites in which stress due to filtration flow is counteracted by forces generated by the actin network in foot processes. Numerous studies within last 20 years have identified actin binding and regulatory proteins as well as integrins as essential components of signaling and actin dynamics at focal adhesions in podocytes, suggesting that some of them may become novel, druggable targets for proteinuric kidney diseases. Here we review evidence supporting the idea that current treatments for chronic kidney diseases beneficially and directly target the podocyte actin cytoskeleton associated with focal adhesions and suggest that therapeutic reagents that target the focal adhesion-regulated actin cytoskeleton in foot processes have potential to modernize treatments for chronic kidney diseases. The presence of high-molecular-weight proteins like albumin in the urine (proteinuria) is the first sign that the selectivity of the kidney filtration barrier has been compromised. Presently, proteinuria is considered one of the strongest risk factors for future loss of kidney function. Most proteinuric kidney diseases and all nephrotic diseases (proteinuria > 3.5 g/d) demonstrate a change in podocyte morphology on an ultrastructural level.1Orth S.R. Ritz E. The nephrotic syndrome.N Engl J Med. 1998; 338: 1202-1211Crossref PubMed Scopus (366) Google Scholar, 2Bergon E. Granados R. Fernandez-Segoviano P. et al.Classification of renal proteinuria: a simple algorithm.Clin Chem Lab Med. 2002; 40: 1143-1150Crossref PubMed Google Scholar Podocyte structure is conventionally divided into 3 types of subcellular compartments: the cell body, the microtubule-driven membrane extensions termed primary processes, and the actin-driven membrane extensions termed foot processes (FPs). FPs of neighboring cells are connected by a podocyte-unique multiprotein complex termed “slit diaphragm.” Podocyte injury often leads to loss of FPs, a process termed “FP effacement,”3Kriz W. Kretzler M. Nagata M. et al.A frequent pathway to glomerulosclerosis: deterioration of tuft architecture-podocyte damage-segmental sclerosis.Kidney Blood Press Res. 1996; 19: 245-253Crossref PubMed Scopus (66) Google Scholar, 4Kriz W. Shirato I. Nagata M. et al.The podocyte's response to stress: the enigma of foot process effacement.Am J Physiol Renal Physiol. 2013; 304: F333-F347Crossref PubMed Scopus (195) Google Scholar and to molecular reorganization or loss of the slit diaphragm.5Somlo S. Mundel P. Getting a foothold in nephrotic syndrome.Nat Genet. 2000; 24: 333-335Crossref PubMed Scopus (235) Google Scholar FP effacement is the result of dysregulation of the actin cytoskeleton, providing a direct link between proteinuria and actin cytoskeleton dynamics. Given the connection between podocyte structure and function, concerted efforts have been made to decipher the 3-dimensional architecture of podocytes. Focused ion beam scanning electron microscopy has identified a tortuous ridge-like prominence which protrudes from either the basal surface of the primary processes or from the cell body.6Ichimura K. Miyazaki N. Sadayama S. et al.Three-dimensional architecture of podocytes revealed by block-face scanning electron microscopy.Sci Rep. 2015; 5: 8993Crossref PubMed Scopus (59) Google Scholar The FPs, previously believed to be terminal projections that only protruded from the primary processes, also branched from this ridge-like prominence. This ridge-like prominence generated a more direct link between the cell body and the FPs than originally thought. The authors suggested that the ridge-like prominences might have served as an adhesion apparatus for the direct attachment of the cell body and the primary processes to the glomerular basement membrane (GBM) and as an apparatus to connect FPs to the cell body. Those novel insights suggest that, in addition to the structural role of podocytes in maintaining kidney filtration, the newly identified ridge-like prominence may play an important role in regulating global organization of the actin cytoskeleton in FPs, as well as cell signaling between neighboring podocytes, the GBM and endothelial cells. Podocytes have remarkable transformational abilities in response to cellular stress. Although podocyte injury often leads to FP effacement, if the podocytes are still attached to the GBM, they have the ability to reform FPs.7Vivarelli M. Massella L. Ruggiero B. Emma F. Minimal change disease.Clin J Am Soc Nephrol. 2017; 12: 332-345Crossref PubMed Scopus (240) Google Scholar Because FP effacement and re-formation are membrane-modifying processes, they are both driven by distinct reorganization of the actin cytoskeleton. During FP effacement, the actin backbone is disassembled and the cellular protrusions lose their delicate appearance to a more squat form. At later stages, a dense layer of actin develops at the GBM-facing side of the cells.8Shirato I. Sakai T. Kimura K. et al.Cytoskeletal changes in podocytes associated with foot process effacement in Masugi nephritis.Am J Pathol. 1996; 148: 1283-1296PubMed Google Scholar This common stress response is seen only on ultrastructural analysis using electron microscopy and can be observed in most proteinuric diseases. During FP regeneration, the dense actin layer is dissolved, and novel FPs branch from the cells.9Subramanian B. Sun H. Yan P. et al.Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury.Kidney Int. 2016; 90: 363-372Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Re-formation of the FPs can be achieved only by induction of actin polymerization in the membrane vicinity. Both FP effacement and reformation require funneling distinct signals into a common hub(s) that controls assembly and disassembly of actin.10Ashworth S. Teng B. Kaufeld J. et al.Cofilin-1 inactivation leads to proteinuria—studies in zebrafish, mice and humans.PLoS One. 2010; 5: e12626Crossref PubMed Scopus (60) Google Scholar, 11Schiffer M. Teng B. Gu C. et al.Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models.Nat Med. 2015; 21: 601-609Crossref PubMed Scopus (89) Google Scholar FPs contain 2 physically and molecularly distinct hubs that control actin dynamics, a slit diaphragm and focal adhesions. Despite the absence of inflammatory cells in biopsy samples, many diseases with direct podocyte involvement are considered mediated by immune cells because treatment with classic immunosuppressant drugs leads to remission in a significant number of patients. This paradigm has been deemed valid for more than 40 years.12Shalhoub R.J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function.Lancet. 1974; 2: 556-560Abstract PubMed Scopus (742) Google Scholar A major conceptual shift from immune-cell-mediated to podocyte-mediated diseases occurred by realizing that many heritable forms of focal segmental glomerulosclerosis (FSGS) are caused by mutations in proteins that are important for podocyte function.13Muller-Deile J. Schiffer M. Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?.Pediatr Nephrol. 2016; 31: 393-405Crossref PubMed Scopus (21) Google Scholar Those discoveries provided direct evidence of the essential role of podocytes in the glomerulus and suggested that direct targeting of the pathogenic pathways within podocytes may have a beneficial effect on glomerular diseases. This original idea was subsequently expanded to argue that current treatments for glomerular diseases, such as those involving angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, as well as diverse immunosuppressants, all exhibit their antiproteinuric effects in part by directly targeting actin cytoskeleton within the podocyte.13Muller-Deile J. Schiffer M. Podocyte directed therapy of nephrotic syndrome—can we bring the inside out?.Pediatr Nephrol. 2016; 31: 393-405Crossref PubMed Scopus (21) Google Scholar One of the earliest attempts to link the effect of antiproteinuric drugs with actin cytoskeleton dynamics in podocytes was in 2008.14Faul C. Donnelly M. Merscher-Gomez S. et al.The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.Nat Med. 2008; 14: 931-938Crossref PubMed Scopus (755) Google Scholar Cyclosporin A (CsA) is an inhibitor of serine/threonine phosphatase calcineurin, known for its role in regulating T-cell activation through regulation of the nuclear factor of activated T-cell (NFAT) signaling. It was suggested that CsA blocked calcineurin-mediated dephosphorylation of the podocyte-specific adaptor protein synaptopodin, which then protected synaptopodin from deleterious cathepsin L-mediated proteolysis in injured podocytes.15Yaddanapudi S. Altintas M.M. Kistler A.D. et al.CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival.J Clin Invest. 2011; 121: 3965-3980Crossref PubMed Scopus (114) Google Scholar Because synaptopodin contributes to RhoA16Asanuma K. Yanagida-Asanuma E. Faul C. et al.Synaptopodin orchestrates actin organization and cell motility via regulation of Rho A signalling.Nat Cell Biol. 2006; 8: 485-491Crossref PubMed Scopus (326) Google Scholar and Cdc4217Yanagida-Asanuma E. Asanuma K. Kim K. et al.Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes.Am J Pathol. 2007; 171: 415-427Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholarsignaling, and because those GTPases are major regulators of the actin cytoskeleton in general (see below), these data suggested that CsA ultimately exhibited a protective effect on the actin cytoskeleton in podocytes by stabilizing the RhoA/Cdc42 signaling pathway. Moreover, CsA has a direct effect on cofilin-1 expression, and CsA also regulates phosphorylation of WAVE1, an actin nucleator and a key regulator of Arp2/3-mediated actin polymerization.18Li X. Ding F. Wang S. Li B. Ding J. Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation.Sci Rep. 2015; 5: 17694Crossref PubMed Scopus (8) Google Scholar, 19Li X. Zhang X. Li X. et al.Cyclosporine A protects podocytes via stabilization of cofilin-1 expression in the unphosphorylated state.Exp Biol Med (Maywood). 2014; 239: 922-936Crossref PubMed Scopus (17) Google Scholar Identification of B7-1 (CD80), a costimulatory receptor present on antigen-presenting cells required to induce T-cell activation also on podocyte membrane, provided the opportunity to test the idea that immunomodulators directly target podocytes in humans. Experiments using diverse animal models and podocyte tissue culture suggested that de novo expression of B7-1 in podocytes initiated their injury by deactivating essential α3β1 integrin.20Reiser J. von Gersdorff G. Loos M. et al.Induction of B7-1 in podocytes is associated with nephrotic syndrome.J Clin Invest. 2004; 113: 1390-1397Crossref PubMed Scopus (459) Google Scholar, 21Yu C.C. Fornoni A. Weins A. Hakroush S. Maiguel D. Sageshima J. et al.Abatacept in B7-1-positive proteinuric kidney disease.N Engl J Med. 2013; 369: 2416-2423Crossref PubMed Scopus (293) Google Scholar Abatacept (CTLA4-Ig), a fusion protein that blocks T-cell activation by binding to B7-1 and B7-2 (CD86) on antigen-presenting cells with high affinity, is a drug licensed for the treatment of rheumatoid arthritis. After an original promising study,21Yu C.C. Fornoni A. Weins A. Hakroush S. Maiguel D. Sageshima J. et al.Abatacept in B7-1-positive proteinuric kidney disease.N Engl J Med. 2013; 369: 2416-2423Crossref PubMed Scopus (293) Google Scholar the responsiveness of FSGS patients to abatacept or to a newer version of the drug named belatacept has been discouraging.22Garin E.H. Reiser J. Cara-Fuentes G. et al.Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis.Pediatr Nephrol. 2015; 30: 469-477Crossref PubMed Scopus (68) Google Scholar In fact, although abatacept effectively reduced the level of activated CD4+ T cells, its administration did not preserve kidney function in the streptozocin-induced model of diabetic nephropathy in mice,23Norlin J. Nielsen Fink L. Helding Kvist P. et al.Abatacept treatment does not preserve renal function in the streptozocin-induced model of diabetic nephropathy.PLoS One. 2016; 11: e0152315Crossref PubMed Scopus (12) Google Scholar further questioning the direct effect of abatacept on podocytes. In contrast to the negative results with immunomodulators that act by blocking T-cell activation, the B-cell-targeting drug rituximab exhibited moderate success in some patients with nephrotic syndrome.24Buscher A.K. Beck B.B. Melk A. et al.Rapid response to cyclosporin a and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome.Clin J Am Soc Nephrol. 2016; 11: 245-253Crossref PubMed Scopus (90) Google Scholar, 25Ravani P. Bonanni A. Ghiggeri G.M. Randomised controlled trial comparing ofatumumab to rituximab in children with steroid-dependent and calcineurin inhibitor-dependent idiopathic nephrotic syndrome: study protocol.BMJ Open. 2017; 7: e013319Crossref PubMed Scopus (21) Google Scholar Rituximab is a chimeric monoclonal antibody against the protein CD20, which is found primarily on the surface of immune system B cells where it acts by destroying them. Fornoni et al.26Fornoni A. Sageshima J. Wei C. et al.Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.Sci Transl Med. 2011; 3: 85ra46Crossref PubMed Scopus (398) Google Scholar suggested that, in CKD patients, rituximab operates in a B-cell-independent manner by directly targeting podocytes. Specifically, the authors hypothesized that rituximab binds sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a lipid-modulating phosphodiesterase. Studies using podocytes in culture suggested that rituximab partially prevented SMPDL3b down-regulation, which was associated with recurrent FSGS. Because levels of SMPDL3b expression affected the actin cytoskeleton in podocytes, the study suggested that rituximab modulates podocyte actin cytoskeleton in an SMPDL3b-dependent manner. The above-mentioned therapeutics were developed to specifically target the immune system. Presently, it is hard to conclude with certainty whether the antiproteinuric effects observed in a subset of patients and/or animal models are due to their effect on podocytes, to immunomodulation, or to both. In contrast to immunomodulators, renin angiotensin aldosterone system (RAAS) blockers are the only generally accepted and most widespread supportive antiproteinuric therapy agents that have a proven influence on kidney function.27Toto R.D. Proteinuria reduction: mandatory consideration or option when selecting an antihypertensive agent?.Curr Hypertens Rep. 2005; 7: 374-378Crossref PubMed Scopus (11) Google Scholar Although their antiproteinuric effect is clearly due to alterations in the blood flow in the glomerulus due to change in blood pressure, it is not surprising that a number of studies also examined the ability of RAAS to alter the actin cytoskeleton in podocytes. Both angiotensin II receptor types 1 (AT1) and 2 (AT2) are expressed in podocytes, and their expression levels are elevated in proteinuric diseases.28Suzuki K. Han G.D. Miyauchi N. et al.Angiotensin II type 1 and type 2 receptors play opposite roles in regulating the barrier function of kidney glomerular capillary wall.Am J Pathol. 2007; 170: 1841-1853Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Durvasula et al.29Durvasula R.V. Petermann A.T. Hiromura K. et al.Activation of a local tissue angiotensin system in podocytes by mechanical strain.Kidney Int. 2004; 65: 30-39Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar showed that RAAS inhibition can lead to reduced cell tonus and decreased apoptosis in an AT1 receptor-mediated fashion in cultured podocytes. This observation functionally supports the older observations that angiotensin II infusion leads to blood pressure-independent proteinuria, changes in chloride conductance of podocytes, and cytoskeletal rearrangement.30Gloy J. Henger A. Fischer K.G. et al.Angiotensin II depolarizes podocytes in the intact glomerulus of the rat.J Clin Invest. 1997; 99: 2772-2781Crossref PubMed Scopus (79) Google Scholar, 31Sharma R. Lovell H.B. Wiegmann T.B. Savin V.J. Vasoactive substances induce cytoskeletal changes in cultured rat glomerular epithelial cells.J Am Soc Nephrol. 1992; 3: 1131-1138PubMed Google Scholar More recent data from Nijenhuis et al.32Nijenhuis T. Sloan A.J. Hoenderop J.G. et al.Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway.Am J Pathol. 2011; 179: 1719-1732Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar suggested a direct negative effect of angiotensin II on podocytes through the NFAT-mediated upregulation of TRPC6 expression, indicating direct prevention of this deleterious cellular effect through angiotensin-converting enzyme inhibition. As for immunomodulating drugs, although these data suggest that RAAS-blockers play a role in altering podocyte structure, given their effect on blood pressure, it is impossible to indisputably attribute their antiproteinuric effect to directly targeting podocytes. Realization that the actin cytoskeleton plays an essential role in maintaining podocytes’ unique structure led to a wide spread effort by the scientific community to decipher both podocyte-specific and canonical signaling pathways essential for regulating its actin cytoskeleton (for comprehensive review, see Perico et al.33Perico L. Conti S. Benigni A. Remuzzi G. Podocyte-actin dynamics in health and disease.Nat Rev Nephrol. 2016; 12: 692-710Crossref PubMed Scopus (117) Google Scholar). As mentioned above, FPs contain 2 molecularly distinct “hubs” that control actin dynamics: a slit diaphragm and focal adhesions. Because glomerular filtration flow represents the highest extravascular fluid flow in the body, the attachment of podocytes to GBM is challenged by both tensile and shear stress forces. Kriz and Lemley34Kriz W. Lemley K.V. Potential relevance of shear stress for slit diaphragm and podocyte function.Kidney Int. 2017; 91: 1283-1286Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar recently suggested a distinct role for the slit diaphragm in balancing the lateral components of the shear stresses on opposing FPs. Because this unique podocyte structure is either altered or lost in most pathological situations, it seems reasonable to suggest that slit diaphragm-specific proteins may not be the best targets for drug therapy for chronic kidney disease (CKD). In contrast, number of studies suggested that focal adhesion proteins have potential to be druggable in CKD. The mechanical forces endured at the sites of focal adhesion (FAs) are believed to result from the retrograde flow of actin in the membrane vicinity, the remodeling of dendritic actin networks into liner filaments array of the stress fibers in the vicinity of adhesions, and the bundling of actin by mysosin II, which stimulates proximal actin assembly (Figure 1). Thus, bidirectional force transmission between the internal cytoskeletal network and the exterior gets directed through the adhesion. A mature focal adhesion contains hundreds of proteins that can be grouped based on their contribution to 4 basic processes: receptor–matrix binding proteins, linkage to actin cytoskeleton, intracellular signal transduction, and actin polymerization (general information on FAs can be found at https://www.mechanobio.info/topics/mechanosignaling/cell-matrix-adhesion/focal-adhesion/).35Reiser J. Sever S. Faul C. Signal transduction in podocytes—spotlight on receptor tyrosine kinases.Nat Rev Nephrol. 2014; 10: 104-115Crossref PubMed Scopus (22) Google Scholar In regard to podocytes, integrin α3αβ1 is essential for maintenance of glomerular structural integrity.36Sterk L.M. de Melker A.A. Kramer D. et al.Glomerular extracellular matrix components and integrins.Cell Adhes Commun. 1998; 5: 177-192Crossref PubMed Google Scholar In contrast, a growing number of studies suggest that one of the hallmarks of podocyte injury is the activation of constitutively inactive αvβ3 integrin (Figure 1),37Wei C. El Hindi S. Li J. et al.Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis.Nat Med. 2011; 17: 952-960Crossref PubMed Scopus (646) Google Scholar which initiated the search for its activating ligands. Soluble urokinase activating receptor (suPAR) has been implicated as one of the ligands for αvβ3 integrin activation in podocytes.37Wei C. El Hindi S. Li J. et al.Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis.Nat Med. 2011; 17: 952-960Crossref PubMed Scopus (646) Google Scholar Although suPAR per se does not seem to be highly pathogenic in wild-type animals, coadministration of suPAR and human autoantibodies against CD40 isolated from patients with recurrent FSGS resulted in proteinuria, FP effacement, and histological evidence of glomerular sclerosis.38Wei C. Sigdel T.K. Sarwal M.M. Reiser J. Circulating CD40 autoantibody and suPAR synergy drives glomerular injury.Ann Transl Med. 2015; 3: 300PubMed Google Scholar, 39Spinale J.M. Mariani L.H. Kapoor S. et al.A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease.Kidney Int. 2015; 87: 564-574Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar No kidney injury was noted in mice deficient in CD40 or in wild-type mice that received blocking antibody to CD40. CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. Circulating anti-CD40 antibody was identified by screening approximately 9000 antigens in pretransplantation sera for their ability to predict posttransplantation FSGS recurrence with high accuracy.40Delville M. Sigdel T.K. Wei C. et al.A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation.Sci Transl Med. 2014; 6: 256ra136Crossref PubMed Scopus (145) Google Scholar Expanding the type of mechanism for αvβ3 integrin-induced podocyte injury, recent studies identified a link between apolipoprotein L1 (ApoL1) and suPAR-driven αvβ3 integrin activation, suggesting formation of a triple complex among suPAR, ApoL1, and αvβ3 integrin.41Kim E.Y. Roshanravan H. Dryer S.E. Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors.Biochim Biophys Acta. 2017; 1863: 2342-2354Crossref PubMed Scopus (28) Google Scholar, 42Hayek S.S. Koh K.H. Grams M.E. et al.A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease.Nat Med. 2017; 23: 945-953Crossref PubMed Scopus (138) Google Scholar In addition, suPAR-induced αvβ3 integrin activation has been recently linked to increase in activity of TRPC6 (a Ca2+-permeable cationic channel), a channel localized to the slit diaphragm.41Kim E.Y. Roshanravan H. Dryer S.E. Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors.Biochim Biophys Acta. 2017; 1863: 2342-2354Crossref PubMed Scopus (28) Google Scholar, 42Hayek S.S. Koh K.H. Grams M.E. et al.A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease.Nat Med. 2017; 23: 945-953Crossref PubMed Scopus (138) Google Scholar This study established a link between αvβ3 integrin signaling at the FAs and activity of slit diaphragm channel. Importantly, an identical effect was observed with sera from FSGS patient but only if the patient was in a relapsed state of disease.41Kim E.Y. Roshanravan H. Dryer S.E. Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors.Biochim Biophys Acta. 2017; 1863: 2342-2354Crossref PubMed Scopus (28) Google Scholar, 42Hayek S.S. Koh K.H. Grams M.E. et al.A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease.Nat Med. 2017; 23: 945-953Crossref PubMed Scopus (138) Google Scholar Furthermore, a study identified periostin as jet anther αvβ3 integrin ligand.43Prakoura N. Kavvadas P. Kormann R. et al.NFkappaB-induced periostin activates integrin-beta3 signaling to promote renal injury in GN.J Am Soc Nephrol. 2017; 28: 1475-1490Crossref PubMed Scopus (42) Google Scholar Periostin is a secreted extracellular matrix protein found in many cancers, where binding of αvβ3 or αvβ5 integrin on cancer cells leads to activation of number of downstream signaling pathways implicated in cell invasion, metastasis, and epithelial–mesenchymal transition.43Prakoura N. Kavvadas P. Kormann R. et al.NFkappaB-induced periostin activates integrin-beta3 signaling to promote renal injury in GN.J Am Soc Nephrol. 2017; 28: 1475-1490Crossref PubMed Scopus (42) Google Scholar By using a combination of bioinformatics, reporter assay, and chromatin immunoprecipitation analyses, it was found that nuclear factor κ β (NFκβ) and other proinflammatory transcription factors induced de novo expression of periostin in vitro and that periostin and β3 integrin colocalized in renal biopsies from patients with antineutrophil cytoplasmic antibodies disease, vasculitis, inflammatory glomerulopathy and in glomeruli of nephrotoxic serum-induced glomerular nephropathy in mice.43Prakoura N. Kavvadas P. Kormann R. et al.NFkappaB-induced periostin activates integrin-beta3 signaling to promote renal injury in GN.J Am Soc Nephrol. 2017; 28: 1475-1490Crossref PubMed Scopus (42) Google Scholar Mice lacking expression of periostin displayed preserved renal function and structure during nephrotoxic serum-induced glomerular nephropathy, and administration of periostin antisense oligonucleotides in wild-type animals with glomerular nephropathy reversed already established proteinuria, diminished tissue inflammation, and improved renal structure. Together, these studies identified several potential therapeutic strategies for treating CKD, such as inhibition/downregulation of αvβ3 integrin, periostin, suPAR, and removal of auto-CD40 antibodies. A monoclonal antibody that blocks αvβ3 integrin ligand occupancy inhibited the progression of albuminuria in diabetic rats and development of nephropathy in diabetic pigs and is currently being tested in patients with CKD.44Maile L.A. Busby W.H. Gollahon K.A. et al.Blocking ligand occupancy of the alphaVbeta3 integrin inhibits the development of nephropathy in diabetic pigs.Endocrinology. 2014; 155: 4665-4675Crossref PubMed Scopus (39) Google Scholar, 45Maile L.A. Gollahon K. Wai C. et al.Blocking alphaVbeta3 integrin ligand occupancy inhibits the progression of albuminuri" @default.
• W2802384383 created "2018-05-17" @default.
• W2802384383 creator A5026721524 @default.
• W2802384383 creator A5051490000 @default.
• W2802384383 date "2018-06-01" @default.
• W2802384383 modified "2023-10-18" @default.
• W2802384383 title "Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases" @default.
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• W2802384383 doi "https://doi.org/10.1016/j.kint.2017.12.028" @default.
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