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Over the years, a very large amount of evidence has accumulated indicating that endothelin (ET)-1 is an important stimulus for inflammation. This is true for a wide range of organ system diseases, including chronic kidney disease. Nonetheless, our understanding of the role and mechanisms by which ET-1 promotes the activation of both the innate and adaptive immune systems is not understood. ET-1 can directly activate neutrophils as well as endothelial cells to stimulate production of chemoattractant factors, such as monocyte chemoattractant factor-1, and increase synthesis of cell adhesion molecules, such as soluble ICAM-1. The mechanisms that trigger these events, however, are less clear. Elevated blood pressure as well as hyperglycemia could be important factors that facilitate ET-1-dependent inflammation. While renal inflammation has not been used as an endpoint for drug development, the rationale for the use of ET antagonists as anti-inflammatory agents in chronic kidney disease is quite strong, based on animal studies and at least one study in humans with nondiabetic nephritis. While the preponderance of evidence suggests that ET(A) selective antagonists are advantageous over combined ET(A/B) receptor blockers, considerably more work needs to be done in order to understand the complex role of ET in renal inflammation.
Copyright © 2011 S. Karger AG, Basel.
Endothelin (ET) 1 is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nmol/L) significantly increased glomerular permeability to albumin, reaching a maximum after 4 hours. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased glomerular permeability to albumin and nephrin excretion rate, effects that were attenuated in rats given an ET(A) receptor antagonist (ABT-627, 5 mg/kg per day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1-infused rats with the selective ET(A) antagonist significantly reduced glomerular permeability to albumin, an effect not observed with acute treatment with a selective ET(B) antagonist. Chronic ET-1 infusion increased glomerular and plasma soluble intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3-positive staining, respectively). These effects were all attenuated in rats given an ET(A) selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ET(A) receptor activation independent of changes in arterial pressure.
Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon. One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB). The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon. In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR, in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.
In the decade since the initial discovery and characterization of endothelin, its biology as a powerful vasoconstrictor has been dramatically demonstrated. Studies have clarified the existence of endothelin isoforms, complex mechanisms of biosynthesis, interaction with specific receptors, and pathogenic implications. We are on the brink of using endothelin antagonism as a clinical treatment for disease processes where endothelin plays an important role, including congestive heart failure and hypertension. Novel observations have been made about the unexpectedly profound contribution endothelins make to normal fetal maturation, especially in cardiac and enteric development.
The endothelin peptides comprise a family of potent and long-lasting vascoconstrictors, to which the renal microcirculation is particularly susceptible. Increased renal endothelin expression is observed after a variety of injurious stimuli, including ischemia, and persists for days after resolution of the initial injury. Autoinduction of its own production is likely to be a central mechanism underlying endothelin's prolonged effects. Furthermore, antagonizing endothelin reveals its role in maintaining the postischemic glomerular dysfunction that typifies ischemic acute renal failure.
Chronic treatment with cyclosporine (CsA) is limited not only by glomerular hypofiltration but also by structural damage. The pathogenesis of these nephrotoxicities was studied in a model of chronic CsA-induced renal damage. Salt-depleted rats were treated with daily CsA (15 mg/kg sc) for approximately 3 weeks, at which time renal function was measured and kidneys were harvested for morphologic assessment. A separate group of rats (CsA + BQ123) were identically treated with CsA but in addition also received simultaneous treatment with a specific endothelin A (EtA) receptor antagonist, BQ123, which was continuously delivered via sc osmotic pump (1 mg/kg per hour) and maintained throughout the study. Chronic CsA treatment caused profound functional and structural damage, although blood pressure was normal (102 +/- 6 mm Hg); GFR was 0.05 +/- 0.02 mL/min per 100 g body wt, and RPF was 0.15 +/- 0.06/100 g body wt. Renal injury was scored on a scale of 0 to 4 and showed dilation/vacuolization of 1.07 +/- 0.29 and tubulointerstitial fibrosis of 0.78 +/- 0.17. Arteriolopathy was present in 78 +/- 4% of arterioles. Chronic antagonism of the EtA receptor preserved renal function: GFR was 0.15 +/- 0.03 mL/min per 100 g body wt, and RPF was 0.32 +/- 0.08/100 g body wt (P < 0.05 for GFR versus CsA). Blood pressure was not affected: 104 +/- 8 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)