Papel do sistema endotelina na nefropatia diabética

Abstract

Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.

Diabetes melito: hiperglicemia crônica e suas complicações

“…O processo de esclerose dos glomérulos renais inicia-se com a multiplicação das células mesangiais, nas quais o transporte de glicose para o meio intracelular não diminui com a hiperglicemia crônica, causando maior concentração citoplasmática de glicose [26][27][28][29][30] .…”

“…O excesso de glicose no meio intracelular ativa a via da PKC, estimulando a síntese de proteínas da matriz extracelular, como a fibronectina, laminina, tenascina e o colágeno. Por causa do aumento da produção celular, ocorre acúmulo de componentes proteicos na matriz extracelular do glomérulo renal, principalmente de colágeno (tipo I e III) e tenascina, com consequente modificação da matriz mesangial e formação do glomérulo renal esclerótico 27,29 .…”

Nitric oxide system and diabetic nephropathy

“…Impairment of the phosphatidylinositide 3-kinases (PI3K) – protein kinase B (AKT) – eNOS – NO pathway as a manifestation of insulin resistance contributes to endothelial dysfunction, predisposing the endothelium to hyper-inflammatory and thrombotic states, while endothelin-1 expression and mitogenic effects are not affected [17]. Exercise, diet, cardiovascular drugs and insulin sensitizers, such as angiotensin-converting enzyme inhibitors, angiotensin receptor inhibitors, and the PPARg agonists, modulate both metabolic and cardiovascular effects of insulin simultaneously by regulating PI3K-AKT-eNOS signaling [18].…”

“…Endothelin-1 acts in the kidney rising vascular resistance, which leads to reduction in blood flux, glomerular filtration rate and inhibition of salt and water reabsorption. It also causes glomerular cellular proliferation and accumulation of extracellular matrix [17]. …”

Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemia

“…Recent studies have demonstrated the role of ET-1 in the initial phase of DN. Specifically, the expression of ET-1 receptors can be stimulated by hyperglycemia 37 . The kidney is an essential site of its production; ET-1 causes increased renal vascular resistance, reduced renal blood flow and glomerular filtration rate, and inhibition of salt and water reabsorption 37 .…”