Intermedin prevents acute heart failure following acute kidney injury by alleviating inflammatory responses

Acute heart failure (AHF) is a common complication of acute kidney injury (AKI), which leads to a poor prognosis in AKI patients. The pathogenesis of AHF is closely related to cardiac inflammatory responses. Intermedin (IMD) has been demonstrated to attenuate cardiac inflammation, however, its role in AHF following AKI (AKI-AHF) remains to be elucidated. We aimed to investigate the effects of IMD on AKI-AHF and to elucidate the underlying mechanisms. We demonstrated that AKI induced by bilateral kidney ischemia-reperfusion injury (IRI) upregulated IMD and its receptors in the kidneys and heart. Following kidney IRI, AHF was more severe in IMD knockout (IMD^-/-) mice compared with wild-type littermates, indicating IMD attenuates AKI-AHF. To clarify whether IMD has a direct effect on the heart, we used bilateral nephrectomy (BNX)-induced AKI model to exclude the influence of the degree of AKI on AHF. The results also showed that the cardiac injury in IMD^-/- mice was more severe than that in IMD^+/+ mice, indicating that IMD has a direct protective effect on the heart. Serum inflammatory mediators were elevated more significantly in IMD^-/- mice compared with IMD^+/+ mice after AKI. Additionally, IMD^-/- mice exhibited enhanced activation of NF-κB, as well as increased expression of inflammatory mediators in cardiac tissue following AKI. In summary, IMD protects AKI-AHF through the reduction of both localized cardiac inflammation and systemic inflammatory responses following kidney IRI. Upregulation of cardiac IMD expression may represent a viable approach to attenuate AKI-AHF and improve the prognosis of AKI, warranting further investigation.