Endothelium-derived endothelin-1 mediates sickle cell nephropathy.

Abstract

Sickle cell nephropathy (SCN) significantly shortens the life expectancy of patients with sickle cell disease (SCD). We previously reported that endothelin-1 (ET-1) and endothelin A receptor (ET) are upregulated in SCN, and ETantagonism mitigates SCN early in the disease progression in a humanized mouse model of SCD. We hypothesized that endothelium-derived ET-1 mediates the progression of SCN and T cell inflammation in the kidney of SCD mice. To test this hypothesis, we first used allogenic bone marrow transplantation from humanized sickle cell mice (HbSS) into endothelial-derived ET-1 knockout (VEET KO) mice, revealing that endothelial-derived ET-1 mitigates SCN and regulates the renal inflammatory response and T cell infiltration. Second, using young (4-5 mo old) and middle-aged (10-15 mo old) HbSS mice lacking endothelial-specific ET-1 (HbSS-VEET KO), we found a temporal maintenance of glomerular filtration rate, reduced infiltration of T cells to the kidney, and reduced progression of SCN. Furthermore, 2-wk ETantagonism in middle-aged HbSS mice reduced infiltration of T cells. Finally, flow cytometric analyses revealed blunting of kidney T helper 17 (T17) cells without a change in kidney T regulatory cells in HbSS-VEET KO mice, suggesting T cell subset-specific regulation by endothelial-derived ET-1 signaling. In vitro studies showed that ETantagonism directly inhibits T17 polarization and IL-17A production, suggesting that in established sickle cell disease, the ETreceptor-T17 cell axis may play a key role in maintenance of fibrosis in SCN. Taken together, these data indicate that endothelial-derived ET-1 mediates the progression of SCN and strengthens the rationale for targeting ET-1 signaling as a new therapeutic approach.