Role of endothelin in chronic renal failure—developments in renal involvement
Department of Nephrology, Charité, Humboldt University, Berlin, Germany.
Correspondence to: C. M. Richter, Charité Campus Benjamin Franklin, Department of Nephrology, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail: Richtercm{at}gmx.de
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Abstract |
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Endothelin (ET)-1 is a potent vasoconstrictor with profibrotic and proinflammatory effects. Increasing evidence suggests that ET-1 and its cognate receptors are involved in a variety of progressive renal disorders, including diabetes, hypertension and glomerulonephritis. Several laboratory studies have demonstrated elevated expression of ET-1, which colocalizes with glomerular and tubulointerstitial injury, in addition to enhanced urinary excretion. Moreover, ET-1 expression correlates with disease severity and renal function. With the availability of ET receptor antagonists, a pathogenetic role has been further corroborated in animal models, demonstrating both structural and functional improvement. Thus, antagonizing the ET system may be useful in major renal pathologies associated with glomerular and tubulointerstitial damage.
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Introduction |
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Endothelin (ET) is a potent vasoconstrictor peptide with profibrotic and pro-inflammatory potential that has been initially discovered in vascular endothelial cells [1]. During the recent years, it has become increasingly clear that a broad spectrum of cells has the ability to produce ET-1 under physiological conditions, and, more importantly, during the course of chronic progressive disorders.
ET-1 is intimately involved in normal renal function, modulating glomerular filtration rate (GFR), solute and water reabsorption along the nephron, and renal acid excretion. Following the discovery of the ET peptides by Yanagisawa et al. [1], however, substantial evidence has accumulated indicating that the ET system is implicated in several forms of chronic renal failure.
Renal glomerular, tubular and interstitial cells have not only the ability to respond to circulating ET-1 via binding to ETA and ETB receptors, but also to produce ET-1 in an autocrine/paracrine manner. During the course of chronic renal diseases, the intrarenal synthesis of ET-1 is remarkably up-regulated along with a modulation of ET receptor subtype expression, particularly at those sites affected by the pathological process. The present minireview will summarize the most impressive findings pointing to a pathogenetic role of the ET system in chronic fibrotic glomerular and tubulointerstitial disorders.
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Role of ET system in chronic renal failure |
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Direct evidence for a causal role of ET-1 in renal fibrosis has been provided by Hocher et al. [2]. Transgenic mice overexpressing human ET-1 in the kidney time-dependently develop glomerulosclerosis, tubulointerstitial fibrosis and renal cysts, which occurs in parallel with a reduction in GFR [2]. These observations strengthen the concept that increased intrarenal ET-1 production is sufficient to cause morphological and functional alterations characteristic for chronic renal failure, rather than being an epiphenomenon during the course of chronic renal disorders. However, this raises the question on the mechanism of increased intrarenal ET-1 production and the mode of action in chronic renal diseases.
Hypertension, diabetes and glomerulonephritis represent the major human pathologies associated with chronic glomerular and tubulointerstitial injury. A common feature in chronic renal disease, either related to immune or non-immune causes, is the progressive loss of functional nephrons. Consequently, those nephrons with initial minor functional impairment undergo hypertrophy, with an increase in single nephron GFR, aiming to maintain total GFR [3]. This process, however, at least in the long-term, initiates a vicious circle, leading to progressive glomerular injury with subsequent glomerular barrier dysfunction [4].
Most likely, proteinuria is causally involved in progressive structural and functional renal deterioration, since the degree of proteinuria directly reflects the severity of renal injury, and therapeutical manoeuvres that reduce proteinuria also slow the underlying disease progress [5]. Elegant work by Benigni and coworkers [6] provided a mechanistic link between glomerular barrier dysfunction and proteinuria, increased intrarenal production of ET-1 and progressive renal failure. In rats, renal mass reduction (5/6 nephrectomy; simulating the loss of functional nephrons) caused a time-dependent increase in proteinuria, which paralleled the up-regulation of intrarenal ET-1 mRNA expression [7]. Accordingly, in vitro exposure of proximal tubular epithelial cells to high-molecular-weight proteins such as albumin, IgG and transferrin elicits a dose-dependent production of ET-1, which is primarily released abluminally into the interstitial compartment, while only a minor portion is secreted luminally and thus appears in the urine [6]. In agreement, systemic levels of ET-1 are elevated in chronic renal failure, and urinary ET-1 excretion is about five times increased compared with healthy subjects [8].
Role of ET system in glomerular fibrosis
Several conditions known to cause progressive glomerular injury have the ability to stimulate intraglomerular ET-1 expression. In streptozotocin-diabetic rats, glomerular ET-1 expression and urinary ET-1 excretion increase markedly [9]. Studies on primary cultures of rat mesangial cells have demonstrated that elevated glucose levels per se are sufficient to stimulate ET-1 promoter activity and ET-1 expression [9]. ET-1 produced by glomerular cells may exert biological effect in an autocrine/paracrine manner on glomerular cells itself, or, via peritubular capillaries, on tubular and interstitial cells (see subsequently). Mesangial cell proliferation and expansion of extracellular matrix are a hallmark in chronic glomerular disease [10]. Interestingly, ET-1 stimulates mesangial cell proliferation and extracellular matrix production [10], thus likely contributing to glomerular pathobiology. In agreement, dual ET antagonism with bosentan prevents matrix deposition and glomerular basement membrane thickening in diabetic rats [11].
Increasing evidence suggests that the ET-1 system is also involved in glomerulosclerosis in hypertension. Several factors instrumental in hypertension, including oxidized LDL, shear stress, vasoconstrictors, reactive oxygen species, growth factors and others have the ability to increase ET-1 production by mesangial cells [10]. Indeed, uninephrectomized, spontaneously hypertensive rats showed increased intraglomerular ET-1 expression, which coincided with intense proteinuria, mesangial expansion and glomerulosclerosis [12]. Interestingly, angiotensin-converting enzyme (ACE) inhibition ameliorated proteinuria and reduced ET-1 expression [12], suggesting that ET-1 may at least partially mediate the detrimental effects of angiotensin II.
Pro-inflammatory cytokines stimulate mesangial ET-1 production [10]. Accordingly, several experimental models of glomerulonephritis have demonstrated an increased glomerular abundance of ET-1 and ET receptors, which occurred in parallel with structural glomerular injury [13, 14]. Conversely, methylprednisolone treatment reduced both ET-1 expression and structural damage suggesting that ET-1 is involved in the inflammatory process. Initial results in NZB/W F1 mice which develop glomerular lesions resembling human lupus nephritis indicate that bosentan treatment is effective, particularly when combined with COX-2 inhibition. Despite being known to reduce ET-1 expression and structural lesions in animal models [13, 14], high-dose corticosteroids may precipitate renal crisis in patients with systemic sclerosis [15, 16]. Thus, it may be difficult to separate causal and secondary effects in animals and to directly extrapolate experimental data to humans.
ET-1 in tubulointerstitial fibrosis
The second major histomorphological alteration in progressive renal failure is tubulointerstitial inflammation and fibrosis. Increased tubulointerstitial ET-1 abundance may result from protein challenge of proximal tubular epithelial cells (mentioned earlier) and from ET-1 produced within glomeruli, reaching the tubulointerstitial compartment via peritubular capillaries originating from efferent arterioles. Locally released ET-1 may trigger renal injury by two mechanisms. First, ET-1 may cause constriction of peritubular capillaries with subsequent hypoxic injury of neighbouring proximal tubules based on their high metabolic demands. Hypoxia, in turn, which is a major stimulus for ET-1 expression, may trigger ET-1 production in tubular epithelial cells, thereby potentially initiating a vicious circle. Secondly, ET-1 is not only a potent vasoconstrictor, but also promotes accumulation of inflammatory cells and extracellular matrix production. Accordingly, activation of nuclear factor (NF)-
B (which drives the expression of many pro-inflammatory cytokines) is prominent in proximal tubules and infiltrating mononuclear cells in rats with intense proteinuria, whereas ET antagonism reduces NF-B activation, interstitial infiltration and renal lesions [17].
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Conclusions |
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TopAbstractIntroductionRole of ET system...ConclusionsReferences |
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The following observations support a pathogenetic role of the ET system in conditions associated with progressive glomerular and tubulointerstitial inflammation and fibrosis, including diabetes, hypertension and glomerulonephritis:
- Persistent proteinuria as present during the course of chronic renal disorders stimulates ET-1 production.
- ET-1, via binding to ETA and ETB receptors, mediates extracellular matrix production, inflammation and vasoconstriction.
- ET receptor antagonism ameliorates renal pathology and improves renal function in animal models.
C.R. received speaker's honorarium for participation at Actelion Winter School 2006.
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References |
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- Yanagisawa M, Kurihara H, Kimura S, et al. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–5.[CrossRef][Medline]
- Hocher B, Thone-Reineke C, Rohmeiss P, et al. (1997) Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–9.[Web of Science][Medline]
- Brenner BM, Meyer TW, Hostetter TH. (1982) Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307:652–9.[Web of Science][Medline]
- Hostetter TH, Rennke HG, Brenner BM. (1982) Compensatory renal hemodynamic injury: a final common pathway of residual nephron destruction. Am J Kidney Dis 1:310–4.[Web of Science][Medline]
- Remuzzi G and Bertani T. (1998) Pathophysiology of progressive nephropathies. N Engl J Med 339:1448–56.
[Free Full Text] - Zoja C, Morigi M, Figliuzzi M, et al. (1995) Proximal tubular cell synthesis and secretion of endothelin-1 on challenge with albumin and other proteins. Am J Kidney Dis 26:934–41.[Web of Science][Medline]
- Benigni A. (2000) Endothelin antagonists in renal disease. Kidney Int 57:1778–94.[CrossRef][Web of Science][Medline]
- Ohta K, Hirata Y, Shichiri M, Kanno K, Emori T, Tomita K, Marumo F. (1991) Urinary excretion of endothelin-1 in normal subjects and patients with renal disease. Kidney Int 39:307–11.[Web of Science][Medline]
- Hargrove GM, Dufresne J, Whiteside C, Muruve DA, Wong NC. (2000) Diabetes mellitus increases endothelin-1 gene transcription in rat kidney. Kidney Int 58:1534–45.[CrossRef][Web of Science][Medline]
- Sorokin A and Kohan DE. (2003) Physiology and pathology of endothelin-1 in renal mesangium. Am J Physiol Renal Physiol 285:F579–89.
[Abstract/Free Full Text] - Chen S, Evans T, Deng D, Cukiernik M, Chakrabarti S. (2002) Hyperhexosemia induced functional and structural changes in the kidneys: role of endothelins. Nephron 90:86–94.[CrossRef][Web of Science][Medline]
- Largo R, Gomez-Garre D, Liu XH, Alonso J, Blanco J, Plaza JJ, Egido J. (1997) Endothelin-1 upregulation in the kidney of uninephrectomized spontaneously hypertensive rats and its modification by the angiotensin-converting enzyme inhibitor quinapril. Hypertension 29:1178–85.
[Abstract/Free Full Text] - Nakamura T, Ebihara I, Fukui M, et al. (1995) Modulation of glomerular endothelin and endothelin receptor gene expression in aminonucleoside-induced nephrosis. J Am Soc Nephrol 5:1585–90.[Abstract]
- Nakamura T, Ebihara I, Fukui M, et al. (1993) Renal expression of mRNAs for endothelin-1, endothelin-3 and endothelin receptors in NZB/W F1 mice. Ren Physiol Biochem 16:233–43.[Web of Science][Medline]
- Kohno K, Katayama T, Majima K, et al. (2000) A case of normotensive scleroderma renal crisis after high-dose methylprednisolone treatment. Clin Nephrol 53:479–82.[Web of Science][Medline]
- Yamanishi Y, Yamana S, Ishioka S, Yamakido M. (1996) Development of ischemic colitis and scleroderma renal crisis following methylprednisolone pulse therapy for progressive systemic sclerosis. Intern Med 35:583–6.[Web of Science][Medline]
- Gomez-Garre D, Largo R, Tejera N, Fortes J, Manzarbeitia F, Egido J. (2001) Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1. Hypertension 37:1171–8.
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