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Endothelin B receptor (ETBR) deficiency may contribute to the progression of diabetic nephropathy (DN) in a streptozotocin (STZ) model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR mice was characterized by increased serum creatinine and urinary albumin, enhanced glomerulosclerosis, and upregulated ET-1 expression compared with STZ-diabetic WT mice. , HG conditioned media (CM) of ETBR GENs promoted mesangial cell proliferation and upregulated ECM-related proteins, and ET-1 knockout in GENs or inhibition of ET-1/ETAR in mesangial cell suppressed mesangial cell proliferation and collagen IV formation. In addition, ET-1 was over-expressed in ETBR GENs and was regulated by NF-kapapB pathway. ET-1/ETBR suppressed NF-kappaB to modulate ET-1 in GENs. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in mesangial cells, and accelerated mesangial cell proliferation and ECM accumulation. Finally, experiments proved inhibition of NF-kappaB pathway ameliorated DN in ETBR mice. These results suggest that in HG-exposed ETBR GENs, suppression of ET-1 binding to ETBR activated NF-kappaB pathway, thus to secrete large amount of ET-1. Due to the communication between GENs and mesangial cells in diabetes, ET-1 binding to ETAR in mesangial cell promoted RhoA/ROCK pathway, thus to accelerate mesangial cell proliferation and ECM accumulation.
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21-Amino-acid peptides produced by vascular endothelial cells and functioning as potent vasoconstrictors. The endothelin family consists of three members, ENDOTHELIN-1; ENDOTHELIN-2; and ENDOTHELIN-3. All three peptides contain 21 amino acids, but vary in amino acid composition. The three peptides produce vasoconstrictor and pressor responses in various parts of the body. However, the quantitative profiles of the pharmacological activities are considerably different among the three isopeptides.
A subtype of endothelin receptor found predominantly in the VASCULAR SMOOTH MUSCLE. It has a high affinity for ENDOTHELIN-1 and ENDOTHELIN-2.
A 21-amino acid peptide produced predominantly within the kidney and intestine, with smaller amounts produced in the myocardium, placenta, and uterus, but the cells of origin are not clear. Endothelin-2 has no unique physiologic functions, as compared with endothelin-1. (N Eng J Med 1995;333(6):356-63)
Metalloendopeptidases which convert BIG ENDOTHELIN to ENDOTHELIN-1.
A 21-amino acid peptide produced in a variety of tissues including endothelial and vascular smooth-muscle cells, neurons and astrocytes in the central nervous system, and endometrial cells. It acts as a modulator of vasomotor tone, cell proliferation, and hormone production. (N Eng J Med 1995;333(6):356-63)
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