Endothelin‐1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species

Abstract

BACKGROUND AND PURPOSEEndothelin-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 APPROACHAdult, 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 RESULTSIn 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 IMPLICATIONSThese 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. AbbreviationsET-1, endothelin-1; HbAS, heterozygous for sickle and Hb A; HbSS, homozygous for sickle Hb; ROS, reactive oxygen species; SAD, HbS Antillies and D-Punjab; SCD, sickle cell disease; SCN, sickle cell nephropathy BJP British Journal of Pharmacology

Intravascular hemolysis and the pathophysiology of sickle cell disease

“…This is also correct. Published data evidence the involvement of oxidative stress (79,100,105,108,113,115,116,121,123,132,134,135), inflammation (9, 22, 27, 32, 101, 105-108, 115, 124-127, 134), dyslipidemia (135)(136)(137)(138), microparticles (89,122,123,139), and vasoactive peptides (110,111,(140)(141)(142)(143). These additional pathways (depicted in Figure 2) are potentially additive or synergistic to intravascular hemolysis-like mechanisms.…”

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice

“…These results suggest that ET A activation contributes to the maintenance of dysfunction of the glomerular filtration barrier in established sickle nephropathy, a finding that is consistent with previous results from our laboratory. 22 We also determined if ETsignaling contributes to the maintenance of tubular injury in SCD, because final urinary albumin excretion is the result of both glomerular filtration and proximal tubular uptake. Thus, we measured urinary excretion of kidney injury marker 1 (KIM-1) and N-acetyl-b-Dglucosaminidase (NAG), markers of proximal tubule injury.…”

“…17 In the kidney, ET-1 has been implicated as a mechanistic contributor to development of proteinuria in various forms of CKD. [18][19][20][21][22] Moreover, the elevated urinary ET-1 excretion reported in patients with SCD correlates with microalbuminuria, 23 suggesting a pathophysiologic link between ET-1 induction and renal injury in SCD. Direct evidence to demonstrate that ET-1 contributes to renal dysfunction in SCD comes from a study by Sabaa and colleagues who reported that SCD mice treated with the dual ET receptor antagonist, bosentan, were protected from hypoxiainduced decreases in renal blood flow and renal inflammation.…”

The spectrum of sickle hemoglobin-related nephropathy: from sickle cell disease to sickle trait

“…ET-1 mediates endothelial dysfunction by reducing NO bioavailability and induces direct injury to podocytes via the ETA receptor [9,10]. In sickle cell mouse models, ET-1 has been demonstrated to mediate glomerular injury via reactive oxygen species, and ETA receptor antagonism appears to afford renal protection [11,12]. In patients with SCD, ET-1 has also been demonstrated to be associated with albuminuria and measures of vascular dysfunction [13].…”