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Endothelin and endothelin antagonists in chronic kidney disease.

Kohan DE, Barton M - Kidney Int. (2014)

Bottom Line: The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020.Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident.Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

ABSTRACT
The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

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Related in: MedlinePlus

Pathophysiological role of endothelin in CKD development. Intrinsic (aging), physico-chemical (acidemia, hypoxia), biochemical (cytokines, oxidative stress, growth factors, procoagulants), metabolic (insulin, hyperglycemia, dyslipidemia), vasoactive (angiotensin II, aldosterone, vasoconstrictors), and pathological factors (proteinuria) enhance renal endothelin-1 (ET-1) production. CKD development is associated with increased formation of renal ET-1 which - primarily via ETA receptors – promotes renal injury and fibrosis through modulation of multiple renal cell types.
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Figure 1: Pathophysiological role of endothelin in CKD development. Intrinsic (aging), physico-chemical (acidemia, hypoxia), biochemical (cytokines, oxidative stress, growth factors, procoagulants), metabolic (insulin, hyperglycemia, dyslipidemia), vasoactive (angiotensin II, aldosterone, vasoconstrictors), and pathological factors (proteinuria) enhance renal endothelin-1 (ET-1) production. CKD development is associated with increased formation of renal ET-1 which - primarily via ETA receptors – promotes renal injury and fibrosis through modulation of multiple renal cell types.

Mentions: Endothelin plays an important role in the development of proteinuria, fibrosis, and CKD progression (6). ET-1 promotes cell proliferation, hypertrophy, inflammation and extracellular matrix accumulation, all of which are important factors in progression of CKD (11, 12). Renal ET-1 production increases in conditions associated with renal disease progression, such as diabetes, insulin resistance, obesity, immune system activation, dyslipidemia, reactive oxygen species formation, nitric oxide deficiency and others (reviewed in (11), Figure 1). Infusion of non-pressor doses of ET-1 increases renal cortical inflammation (ICAM-1, MCP-1 and macrophages) (13) as well as podocyte effacement and urinary albumin excretion (14), effects that are largely prevented by concomitant treatment with an ETA antagonist (13, 14). Endothelin-1 also increases formation of other vasoconstrictors and growth factors (such as angiotensin II) (15). In turn, angiotensin II activates renal ET-1 formation (16), thereby creating a positive feedback loop. Of note, ET-1 also appears to be involved in the priming effect of acute ischemic renal injury on future CKD development, and this effect that can be largely prevented by blocking ETA (17).


Endothelin and endothelin antagonists in chronic kidney disease.

Kohan DE, Barton M - Kidney Int. (2014)

Pathophysiological role of endothelin in CKD development. Intrinsic (aging), physico-chemical (acidemia, hypoxia), biochemical (cytokines, oxidative stress, growth factors, procoagulants), metabolic (insulin, hyperglycemia, dyslipidemia), vasoactive (angiotensin II, aldosterone, vasoconstrictors), and pathological factors (proteinuria) enhance renal endothelin-1 (ET-1) production. CKD development is associated with increased formation of renal ET-1 which - primarily via ETA receptors – promotes renal injury and fibrosis through modulation of multiple renal cell types.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4216619&req=5

Figure 1: Pathophysiological role of endothelin in CKD development. Intrinsic (aging), physico-chemical (acidemia, hypoxia), biochemical (cytokines, oxidative stress, growth factors, procoagulants), metabolic (insulin, hyperglycemia, dyslipidemia), vasoactive (angiotensin II, aldosterone, vasoconstrictors), and pathological factors (proteinuria) enhance renal endothelin-1 (ET-1) production. CKD development is associated with increased formation of renal ET-1 which - primarily via ETA receptors – promotes renal injury and fibrosis through modulation of multiple renal cell types.
Mentions: Endothelin plays an important role in the development of proteinuria, fibrosis, and CKD progression (6). ET-1 promotes cell proliferation, hypertrophy, inflammation and extracellular matrix accumulation, all of which are important factors in progression of CKD (11, 12). Renal ET-1 production increases in conditions associated with renal disease progression, such as diabetes, insulin resistance, obesity, immune system activation, dyslipidemia, reactive oxygen species formation, nitric oxide deficiency and others (reviewed in (11), Figure 1). Infusion of non-pressor doses of ET-1 increases renal cortical inflammation (ICAM-1, MCP-1 and macrophages) (13) as well as podocyte effacement and urinary albumin excretion (14), effects that are largely prevented by concomitant treatment with an ETA antagonist (13, 14). Endothelin-1 also increases formation of other vasoconstrictors and growth factors (such as angiotensin II) (15). In turn, angiotensin II activates renal ET-1 formation (16), thereby creating a positive feedback loop. Of note, ET-1 also appears to be involved in the priming effect of acute ischemic renal injury on future CKD development, and this effect that can be largely prevented by blocking ETA (17).

Bottom Line: The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020.Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident.Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.

ABSTRACT
The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.

Show MeSH
Related in: MedlinePlus