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Endothelin‐1 mediates glomerular and tubular injury in sickle cell mice
Author(s) -
Kasztan Malgorzata,
Sun ChiaoWang,
Townes Tim M.,
Pollock David M.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1220.7
Subject(s) - medicine , endocrinology , albuminuria , excretion , proteinuria , microalbuminuria , nephropathy , endothelin receptor , renal function , ambrisentan , receptor , kidney , bosentan , diabetes mellitus
Sickle nephropathy (SN) is associated with structural and functional abnormalities in kidneys that lead to albuminuria/proteinuria, a major mortality risk factor in sickle cell disease (SCD). Elevated urinary endothelin‐1 (ET‐1) excretion reported in SCD patients correlates with microalbuminuria, suggesting a pathophysiological link between ET‐1 and development and progression of SN. The aim of the study was to determine whether ET‐1 contributes to glomerular and tubular injury in SCD and if ET A receptors blockade ameliorates these damages. Experiments utilized 14 week old humanized sickle cell mice (HbSS) and genetic controls (HbAA). Ambrisentan (ET A antagonist), A‐182086 (ET A/B antagonist) or vehicle was administrated via drinking water (10mg/kg/day) for 10 (beginning at weaning) or 2 weeks (beginning at 12 week of age). Glomeruli were isolated for direct permeability measurements as a volume response to an oncopressive medium generated by changing concentrations of albumin. Markers of glomerular and tubular injury were measured in 24h urine samples. Administration of ambrisentan for 2 weeks significantly reduced elevated P alb (0.22±0.03 vs. 0.48±0.05), urinary albumin (20.2±3.9 vs. 68.5±20.7μg/24h) as well as markers of tubular injury excretion: KIM‐1(171.3± 13.4 vs. 347±53 pg/24h) and NAG (3.07±1.9 vs. 15.9±1.5 U/L) in HbSS mice. Treatment with the dual ET A/B receptor antagonist had similar effect on P alb , however there was no effect on the excretion of the markers of glomerular and tubular injury. Administration of ambrisentan for 10 weeks significantly reduced elevated P alb (0.14±0.03 vs. 0.52±0.04), markers of glomerular injury: albumin (17.2±4.6 vs. 38.7±5.8μg/24h) and protein (0.74± 0.17 vs. 3.23± 0.4mg/24h), as well as markers of tubular injury excretion: KIM‐1(96.1± 21.6 vs. 373±111.5pg/24h) and NAG (5.8±2.1 vs. 14.5±1.2 U/L) in HbSS mice. Treatment with the dual ET A/B receptor antagonist had similar effect on P alb , however there was no effect on the excretion of the markers of glomerular and tubular injury. Neither antagonist altered any of the measured parameters in HbAA mice. These data support the hypothesis that ET‐1 contributes to the development and progression of sickle cell nephropathy and support the use of chronic ET A antagonism as a prospective treatment for sickle cell nephropathy. Support or Funding Information This work was supported by the program project grant on The Role of Endothelin‐1 in Sickle Cell Disease (U01 HL117684).