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Review
. 2015 Mar;35(2):156-67.
doi: 10.1016/j.semnephrol.2015.02.005.

Endothelin and the glomerulus in chronic kidney disease

Matthias Barton  1 , Andrey Sorokin  2
Affiliations
Review

Endothelin and the glomerulus in chronic kidney disease

Matthias Barton et al. Semin Nephrol. 2015 Mar.

Abstract

Endothelin-1 (ET-1) is a 21-amino acid peptide with mitogenic and powerful vasoconstricting properties. Under healthy conditions, ET-1 is expressed constitutively in all cells of the glomerulus and participates in homeostasis of glomerular structure and filtration function. Under disease conditions, increases in ET-1 are critically involved in initiating and maintaining glomerular inflammation, glomerular basement membrane hypertrophy, and injury of podocytes (visceral epithelial cells), thereby promoting proteinuria and glomerulosclerosis. Here, we review the role of ET-1 in the function of glomerular endothelial cells, visceral (podocytes) and parietal epithelial cells, mesangial cells, the glomerular basement membrane, stromal cells, inflammatory cells, and mesenchymal stem cells. We also discuss molecular mechanisms by which ET-1, predominantly through activation of the ETA receptor, contributes to injury to glomerular cells, and review preclinical and clinical evidence supporting its pathogenic role in glomerular injury in chronic renal disease. Finally, the therapeutic rationale for endothelin antagonists as a new class of antiproteinuric drugs is discussed.

Keywords: ERA; FSGS; GFR; albuminuria; blood pressure; chronic kidney disease; endothelin; endothelin receptor antagonists; epithelial cell; glomerulus; mesangial cells; podocyte; proteinuria.

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Figures

Figure 1
Figure 1
Artist's impression of the structure and cellular components of the glomerulus. The cell types, glomerular components, and vascular structures are indicated. Original pencil drawing by Elena Sorokina (2014).
Figure 2
Figure 2
Schematic representation of structural components of the glomerulus and the actions and interactions of ET-1 (yellow) between the glomerular capillary basement membrane (GBM, orange), the glomerular endothelial cells (GEC, blue), the glomerular podocytes (grey) and the slit diaphragm (green). The drawing is based on a concept of intracellular glomerular communication adapted from Kalluri , and depicts the main ET-1 signaling mechanisms contributing to podocyte and glomerular injury as previously proposed by one of the authors . ET-1 is produced and released from cells on both sides of the GBM, namely glomerular endothelial cells (GEC) and podocytes and affects cellular components of the glomerular capillary. ET-1 released from GEC interacts with the GBM (1), with the slit diaphragm (2), and with podocytes (3). ET-1 release and signaling events may also occur in the reverse direction. Finally, ET-1 released from podocytes interacts with the GBM and vice versa (4). Within the podocyte, ET-1 activates ETA receptors (ETA –R), promoting inflammation, glomerular injury, and sclerosis through MAPKs p38 and p44/p42 pathways (5); ET also stimulates synthesis of the growth-promoter and cdk-inhibitor p21waf/cip1, and pro-inflammatory NF-kappa B (6). ET-1, via ETA receptors, also mediates disruption of the F-actin cytoskeleton (7) and promotes dysfunction of the slit diaphragm (green) involving activation of the Rho-kinase and PI3-kinase pathways. Reproduced from Barton M. Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. Biochim Biophys Acta – Molecular Basis of Disease. 2010; 1802:1203-13, with permission of the publisher.
Figure 3
Figure 3
Effects of treatment with an ET receptor antagonist on established, age-dependent development of focal-segmental glomerulosclerosis (FSGS). Shown are histologic (A, B) or electron microscopic (C-F) sections of glomeruli of aged rats with established FSGS, either untreated (left) or after 4 weeks of treatment with an ETA receptor-selective antagonist (ERA, darusentan (right panels). Compared with untreated rats, ERA treatment for 4 weeks resulted in partial reversal of renal aging. A:, In untreated rats, moderate mesangial matrix expansion and hypertrophy of podocytes with enlarged nuclei, prominent nucleoles (arrow), and many intra-cytoplasmatic vesicles (open arrow) are visible, compatible with podocyte activation in response to injury. B: Following ERA treatment, glomerular injury was reduced, mesangial matrix expansion and podocyte hypertrophy and activation were milder compatible indicative of regression of glomerular aging (Bar, 50 μm). Panels C-F show representative transmission electron micrographs of podocytes and glomerular basement membranes. C: Without treatment, glomerular basement membrane hypertrophy and injury and detachment of podocytes is visible. E: High-power micrograph indicating thickening of glomerular capillary basement membrane with podocyte detachment. Injury of podocytes is characterized by hypertrophy, inclusion of cytoplasmatic absorption droplets due to vacuolar degeration, and diffuse effacement of foot processes. D: ERA treatment for four weeks was associated with partial improved attachment of the podocyte to the basement membrane and complete regression of GBM hypertrophy of the glomerular capillary. F: High-power micrograph showing partial reversal of podocyte aging after ERA treatment. Treatment was associated with a reduction of podocyte injury and complete disappearance of intra-cytoplasmatic vesicles which is also evident in panel B. Reproduced from Ortmann J, Amann K, Brandes RP, Kretzler M, Münter K, Parekh N, Traupe T, Lange M, Lattmann T, Barton M. Role of podocytes for the reversal of glomerulosclerosis and proteinuria in the aging kidney after endothelin inhibition. Hypertension 2004; 44: 974-981, with permission of the publisher.
Figure 4
Figure 4
ET signaling and actions in glomerular mesangial cells. Shown are signaling pathways involved in ET-1-mediated proliferation and contraction of GMC. Black lines indicate signaling processes, green arrows show translocation, red arrows specify inhibitory influence. ADAM, a disintegrin and metalloprotesase domain secretase; BCAR3, breast cancer anti-estrogen resistance 3; βPix, PAK-interacting exchange factor β; CAM, calmodulin; caMKII, calcium-dependent protein kinase; DAG, diacyl glycerol; ET-1, endothelin-1; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FOXO3a, forkhead box O3; GMC, glomerular mesangial cell; Grb2, growth factor receptor-bound protein-2; IP3, inositol triphosphate; Mek, mitogen-activated protein kinase kinase; p130Cas, Crk-associated substrate; p27Kip1, cyclin-dependent kinase inhibitor 1B; p38, p38 MAP kinase; p52Shc, p52 isoform of the SHC-transforming protein-1; p66Shc, p66 isoform of the SHC-transforming protein-1; PDGF, platelet-derived growth factor; PKC, protein kinase C, PLC, phospholipase C; Pyk2, protein tyrosine kinase 2; Raf, raf kinase; RAS, ras protein; Sos, son of sevenless homolog 1; Src, proto-oncogene tyrosine-protein kinase Src; TRPC, transient receptor potential canonical channel. P indicates phosphorylation, GTP indicates guanosine triphophate.
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