Key result
Deletion of the myeloid endothelin-B receptor in mice significantly protected against angiotensin II-mediated kidney and eye injury compared to controls.
Why the study?
Because early hypertensive response to angiotensin-II was amplified in mice deficient of myeloid endothelin-B receptors, researchers investigated whether these mice would display enhanced end-organ injury.
Does deletion of myeloid endothelin-B receptors prevent angiotensin II-mediated organ injury in mice?
Does deletion of myeloid endothelin-B receptors prevent angiotensin II-mediated organ injury in mice?
Deletion of myeloid endothelin-B receptors protects against angiotensin II-mediated organ injury by promoting a natriuretic switch and anti-inflammatory macrophage polarization.
Myeloid endothelin-B receptor deletion may attenuate angiotensin II-induced organ injury in mice; leaves open translation to human hypertension or kidney disease.
The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ET B ) receptors (LysM-Cre Ednrb lox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-Cre Ednrb lox/lox and littermate controls ( Ednrb lox/lox) for six weeks. Unexpectedly, LysM-Cre Ednrb lox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-Cre Ednrb lox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-Cre Ednrb lox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-Cre Ednrb lox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ET B signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-Cre Ednrb lox/lox mice than in controls. At six weeks, macrophages from LysM-Cre Ednrb lox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrb lox/lox mice. Thus, myeloid cell ET B receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.
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Guyonnet et al. (2020) studied Angiotensin II-mediated organ injury. Myeloid endothelin-B receptor deletion vs. Littermate controls (Ednrb lox/lox) was evaluated on Organ injury (proteinuria, glomerulosclerosis, inflammation, retinal hemorrhages). Deletion of the myeloid endothelin-B receptor in mice significantly protected against angiotensin II-mediated kidney and eye injury compared to controls.
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