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 A ) are up-regulated in SCN, and ET A antagonism 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 utilized 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, regulates the renal inflammatory response, and T cell infiltration. Second, utilizing young (4-5 months old) and middle-aged (10-15 months 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, two-week ET A antagonism in middle-aged HbSS mice reduced infiltration of T cells. Finally, flow cytometric analyses revealed blunting of kidney T helper 17 (T H 17) 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 ET A antagonism directly inhibits T H 17 polarization and IL-17A production suggesting that in established sickle cell disease, the ET A receptor-T H 17 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.
Kasztan et al. (Mon,) studied this question.