Endothelium-derived endothelin-1 mediates sickle cell nephropathy

Area of Science:

• Nephrology
• Immunology
• Vascular Biology

Background:

• Sickle cell nephropathy (SCN) is a severe complication of sickle cell disease (SCD), reducing patient life expectancy.
• Endothelin-1 (ET-1) and its receptor ET_A are implicated in SCN pathogenesis.
• Previous studies suggest ET_A antagonism may mitigate early SCN in a mouse model.

Purpose of the Study:

• To investigate the role of endothelium-derived ET-1 in mediating SCN progression and renal T cell inflammation in SCD.
• To explore the therapeutic potential of targeting the ET-1 pathway in SCN.

Main Methods:

• Utilized allogenic bone marrow transplantation from humanized sickle cell mice into endothelial-derived ET-1 knockout (VEET KO) mice.
• Examined young and middle-aged HbSS mice lacking endothelial-specific ET-1 (HbSS-VEET KO).
• Administered ET_A antagonism in middle-aged HbSS mice and performed flow cytometric analyses and in vitro studies.

Main Results:

• Endothelial-derived ET-1 was found to mitigate SCN, regulate renal inflammation, and reduce T cell infiltration in the kidney.
• HbSS-VEET KO mice exhibited maintained glomerular filtration rate, reduced T cell infiltration, and slower SCN progression.
• ET_A antagonism reduced T cell infiltration, and specifically blunted kidney T helper 17 (T_H17) cell polarization and IL-17A production.

Conclusions:

• Endothelial-derived ET-1 plays a critical role in mediating SCN progression and kidney T cell inflammation in SCD.
• Targeting the ET_A receptor-T_H17 cell axis presents a promising therapeutic strategy for SCN.
• These findings support ET-1 signaling as a novel therapeutic target for sickle cell nephropathy.