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Endothelin‐1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species
Author(s) -
Brett Heimlich J,
Speed Joshua S,
O'Connor Paul M,
Pollock Jennifer S,
Townes Tim M,
Meiler Steffen E,
Kutlar Abdullah,
Pollock David M
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13380
Subject(s) - endocrinology , medicine , receptor , renal cortex , nephropathy , endothelin receptor , sickle cell anemia , receptor antagonist , biology , kidney , antagonist , disease , diabetes mellitus
Background and Purpose Endothelin‐1 (ET‐1) is increased in patients with sickle cell disease and may contribute to the development of sickle cell nephropathy. The current study was designed to determine whether ET‐1 acting via the ET A receptor contributes to renal injury in a mouse model of sickle cell disease. Experimental Approach Adult, humanized HbSS (homozygous for sickle Hb) mice had increased ET‐1 mRNA expression in both the cortex and the glomeruli compared with mice heterozygous for sickle and Hb A (HbAS controls). In the renal cortex, ET A receptor mRNA expression was also elevated in HbSS (sickle) mice although ET B receptor mRNA expression was unchanged. Ligand binding assays confirmed that sickle mice had increased ET A receptors in the renal vascular tissue when compared with control mice. Key Results In response to PKC stimulation, reactive oxygen species production by isolated glomeruli from HbSS sickle mice was increased compared with that from HbSA controls, an effect that was prevented by 1 week in vivo treatment with the selective ET A antagonist, ABT‐627. Protein and nephrin excretion were both elevated in sickle mice, effects that were also significantly attenuated by ABT‐627. Finally, ET A receptor antagonism caused a significant reduction in mRNA expression of NADPH oxidase subunits, which may contribute to nephropathy in sickle cell disease. Conclusions and Implications These data support a novel role for ET‐1 in the progression of sickle nephropathy, specifically via the ET A receptor, and suggest a potential role for ET A receptor antagonism in a treatment strategy.