Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells
Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-β receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis. Emerging evidence of crosstalk between glomerular cells in pathological settings provides opportunities for novel therapeutic discovery. Here we investigated underlying mechanisms of early events leading to filtration barrier defects of podocyte and glomerular endothelial cell crosstalk in the mouse models of primary podocytopathy (podocyte specific transforming growth factor-β receptor 1 signaling activation) or Adriamycin nephropathy. We found that glomerular endothelial surface layer degradation and albuminuria preceded podocyte foot process effacement. These abnormalities were prevented by endothelin receptor-A antagonism and mitochondrial reactive oxygen species scavenging. Additional studies confirmed increased heparanase and hyaluronoglucosaminidase gene expression in glomerular endothelial cells in response to podocyte-released factors and to endothelin-1. Atomic force microscopy measurements showed a significant reduction in the endothelial surface layer by endothelin-1 and podocyte-released factors, which could be prevented by endothelin receptor-A but not endothelin receptor-B antagonism. Thus, our studies provide evidence of early crosstalk between activated podocytes and glomerular endothelial cells resulting in loss of endothelial surface layer, glomerular endothelial cell injury and albuminuria. Hence, activation of endothelin-1-endothelin receptor-A and mitochondrial reactive oxygen species contribute to the pathogenesis of primary podocytopathies in experimental focal segmental glomerulosclerosis. Translational StatementOur findings provide compelling evidence that podocyte activation and pathologic crosstalk with endothelial cells via endothelin-1 results in dysfunction and loss of endothelial surface layer (glycocalyx), and this event may underlie early albuminuria in early glomerular disease. Our findings provide compelling evidence that podocyte activation and pathologic crosstalk with endothelial cells via endothelin-1 results in dysfunction and loss of endothelial surface layer (glycocalyx), and this event may underlie early albuminuria in early glomerular disease. Microalbuminuria represents an early biological marker of endothelial dysfunction, and endothelial cell dysfunction can drive progression of kidney disease.1Stehouwer C.D. Smulders Y.M. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms.J Am Soc Nephrol. 2006; 17: 2106-2111Crossref PubMed Scopus (336) Google Scholar, 2Fioretto P. Stehouwer C.D. 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TGFbeta-induced actin cytoskeleton rearrangement in podocytes is associated with compensatory adaptation of mitochondrial energy metabolism.Nephron. 2015; 131: 278-284Crossref PubMed Scopus (11) Google Scholar apoptosis, and podocyte depletion.12Schiffer M. Bitzer M. Roberts I.S. et al.Apoptosis in podocytes induced by TGF-beta and Smad7.J Clin Invest. 2001; 108: 807-816Crossref PubMed Scopus (544) Google Scholar, 13Schiffer M. Mundel P. Shaw A.S. et al.A novel role for the adaptor molecule CD2-associated protein in TGF-beta-induced apoptosis.J Biol Chem. 2004; : 37004-37012Crossref PubMed Scopus (180) Google Scholar In a mouse model of focal segmental glomerulosclerosis (FSGS) where podocyte-specific TGF-β receptor 1 (TGF-βR1) activation induces progressive glomerular disease and renal failure, we have earlier demonstrated release of endothelin-1 (Edn1) by podocytes, followed by increased endothelin receptor-A (EdnrA)–mediated mitochondrial oxidative stress and dysfunction of adjacent glomerular endothelial cells (GECs), which in response, release factor(s) that mediate damage and depletion of adjacent podocytes.14Daehn I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar A similar stressed endothelial-to-podocyte crosstalk could also underlie segmental lesions in diabetic kidney disease (DKD).15Qi H. Casalena G. Shi S. et al.Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility.Diabetes. 2017; 66: 763-778Crossref PubMed Scopus (122) Google Scholar Here, we provide evidence of early GEC injury and ESL degradation in response to podocyte TGF-βR1 signaling activation. Podocyte-derived Edn1 interacted with increased GEC EdnrA expression resulting in mitochondrial reactive oxygen species (ROS) and activation of ESL degradation and remodeling pathways. Together, these crosstalking events could underlie in glomerular to albumin in kidney disease. We the of podocyte-specific activation of TGF-βR1 signaling in I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar In this mouse TGF-βR1 signaling demonstrated to be specific to podocytes.14Daehn I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar showed in and of with analysis the endothelial H. Casalena G. Shi S. et al.Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility.Diabetes. 2017; 66: 763-778Crossref PubMed Scopus (122) Google Scholar confirmed increased lesions with lesions to of and and of podocyte foot were to of with in the podocyte foot but significant were to in by microscopy of with a of podocyte foot and glomerular I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar podocyte in increased to and oxidative stress H. Casalena G. Shi S. et al.Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility.Diabetes. 2017; 66: 763-778Crossref PubMed Scopus (122) Google to of induced segmental glomerulosclerosis by and glomerulosclerosis with fibrosis by These endothelial injury and dysfunction by podocyte activation TGF-βR1 significant albuminuria of podocyte We that crosstalk results in GEC injury and albuminuria. the signaling in response to podocyte TGF-βR1 activation in we analysis of growth factor-β receptor 1 signaling activation in podocytes induces in in of by microscopy in and transforming growth factor-β receptor 1 signaling activation in podocytes with and of endothelial endothelial of podocytes in A endothelial 1 endothelial cell and to of endothelial cells to of and of of The of podocyte foot of with or microscopy of of endothelial cell and of in and to in and and 1 in and in and of this the of this We the early of by with and these for and of protein the of an endothelial growth factor et a protein for and endothelial cells in cells and PubMed Scopus Google Scholar We on an in were associated with and were not associated with et TGF-beta signaling and glomerular dysfunction in diabetic 2015; 64: PubMed Scopus Google Scholar in were to The were to for the were and of and degradation loss and of the ESL The of for and expression of in is in and that loss and of ESL in glomerular on TGF-βR1 activation in podocytes, we ESL in by V. E. Tenstad O. et glomerular endothelial cell coat is essential for glomerular Int. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar microscopy of the the of the ESL showed a and significant loss of ESL of that with and We to which a of the I. D. and function of endothelial glycocalyx layer in PubMed Scopus (97) Google Scholar and and a significant reduction of of with of growth factor-β receptor 1 signaling in podocytes results in the loss of the endothelial surface layer (ESL) by endothelin receptor-A and mitochondrial reactive oxygen of and for with with or a mitochondrial reactive oxygen species 1 or endothelin receptor-A to and Adriamycin with or or with or to glomerular in glomerular endothelial cells and with for and and with and and of and with to of with or to and of this the of this EdnrA have to prevent glycocalyx loss in with A. et albuminuria by the glomerular endothelial glycocalyx barrier in diabetic PubMed Scopus Google Scholar, M. O. et induces by of the glomerular Am Soc Nephrol. PubMed Scopus Google Scholar We have an in EdnrA expression in of experimental and and EdnrA antagonism prevented GEC mitochondrial oxidative and podocyte I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar, H. Casalena G. Shi S. et al.Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility.Diabetes. 2017; 66: 763-778Crossref PubMed Scopus (122) Google Scholar We In is in podocytes and in O. M. A. et of endothelin-1 on podocytes diabetic glomerulosclerosis.J Am Soc Nephrol. 2014; PubMed Scopus Google Scholar, M. T. of endothelin receptor and in the 2006; PubMed Scopus Google Scholar expression in with TGF-βR1 signaling activation in A loss of to of podocyte our I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar expression in with demonstrated a and significant in EdnrA and a of expression we Edn1 expression in glomerular cells that cells glomerular increased Edn1 expression of EdnrA were and of cells expression of of and expression These results on of podocytes by in is a in Edn1 expression by podocytes with the increased EdnrA by which is with our I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar of with a specific EdnrA S. M. et al.A novel and in PubMed Scopus Google Scholar or a the glomerular and also induced to and prevented increased to and These that ESL loss of increased mitochondrial I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar which in could in the early albuminuria of and We the of by in Adriamycin model of podocyte and experimental S. et al.A on determines to in the Natl Acad Sci U S A. PubMed Scopus Google Scholar We confirmed albuminuria and in these in Daehn et I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar a significant in glomerular that by with and and and also to and and to and I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar Edn1 on activation in and in we have via signaling I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar We that Edn1 is a of GEC stress via we the of Edn1 on cell surface expression of Edn1 of and of endothelial cells mouse Int. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar cell to Edn1 for in an in EdnrA expression of Edn1 in an of Edn1 In the of were the of crosstalking factors activated podocytes on receptor expression on we with podocytes with or for EdnrA and expression in the in EdnrA increased in and we an in Edn1 We force on to the in of the ESL cells to or that may the ESL Atomic force microscopy in of 2011; PubMed Scopus Google Scholar, A. 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Our that ESL degradation and remodeling to endothelial dysfunction, which early in disease Hence, to prevent endothelial dysfunction may be more demonstrated with endothelial growth which to diabetic by damage to the GEC glycocalyx of endothelial growth factor in S. et endothelial growth is and endothelial glycocalyx in diabetic Am Soc Nephrol. 2015; PubMed Scopus Google Scholar Our is to that the loss of ESL is associated with podocyte Edn1 degradation and in via also to loss of ESL in and in that increased GEC EdnrA signaling in these models is associated with mitochondrial A. et oxidative stress in Sci 2006; PubMed Scopus (97) Google Scholar, via and mitochondrial reactive oxygen PubMed Scopus Google Scholar In to our that the Edn1 EdnrA and on podocytes resulting in microalbuminuria in experimental O. M. A. et of endothelin-1 on podocytes diabetic glomerulosclerosis.J Am Soc Nephrol. 2014; PubMed Scopus Google Scholar The that increased expression by podocytes is via EdnrA in M. O. et induces by of the glomerular Am Soc Nephrol. PubMed Scopus Google Scholar we not in expression by podocytes with TGF-β the selective EdnrA receptor the of the ESL in of diabetic and prevented A. et albuminuria by the glomerular endothelial glycocalyx barrier in diabetic PubMed Scopus Google Scholar The that the reduction of the endothelial glycocalyx in diabetic by increased glomerular expression of by A. et albuminuria by the glomerular endothelial glycocalyx barrier in diabetic PubMed Scopus Google Scholar We demonstrated that Edn1 GEC EdnrA in and in experimental are for I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar, H. Casalena G. 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Nystrom J. insights crosstalk in the Opin Nephrol Hypertens. 2017; PubMed Scopus Google Scholar, H. in glomerular injury and Opin Nephrol Hypertens. 2015; Google Scholar, I.S. endothelial cells stress and with podocytes in the development of diabetic kidney PubMed Scopus Google Scholar Here we that pathologic crosstalk between activated podocytes and early of glomerular disease on increased mitochondrial and activation of ESL may underlie early glomerular an to potential in for chronic kidney disease. I. Casalena G. Zhang T. et al.Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis.J Clin Invest. 2014; 124: 1608-1621Crossref PubMed Scopus (189) Google Scholar were or in were with or in a and I. Casalena G. 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