A peptide from Boletus griseus‐Hypomyces chrysospermus protects against hypertension and associated cardiac and renal damage through modulating RAAS and intestinal microbiota

Abstract Hypertension is a major risk factor for many cardiovascular diseases, which can lead to kidney and heart disease, stroke, and premature death. Inhibiting angiotensin‐converting enzyme (ACE) activity is an effective method to relieve hypertension. Previously, we screened an active peptide KYPHVF (KF6) from Boletus griseus‐Hypomyces chrysospermus with excellent ACE inhibitory activity. This study further evaluated the antihypertensive activity of the KF6 in vivo. KF6 at 10 mg/kg and Captopril (CAP, a positive control) at 10 mg/kg were administrated to spontaneous hypertensive rats (SHRs) for 5 weeks. The results demonstrated that KF6 effectively lowered both diastolic blood pressure (DBP) and systolic blood pressure (SBP), and decreased ACE, AGT, ALD, and ANG II levels in the serum of SHRs. Furthermore, both cardiac and renal injury of SHRs were ameliorated by KF6 through inhibiting fibrosis, inflammation, and oxidative stress. Moreover, KF6 inhibited ACE‐ANG II‐AT1 axis while activating the ACE2‐Ang (1‐7)‐MAS1L pathway, two mutually antagonistic axes of RAAS, in the kidney and heart of SHRs. Additionally, KF6 improved intestinal microbiota composition, mainly by increasing the abundance of Prevotella and Phascolarctobacterium while decreasing the abundance of Alistipes , Clostridium_IV , Nosocomiicoccus , and Allobaculum . Overall, KF6 is a promising ACE inhibitory peptide for lowering blood pressure and mitigating hypertension‐related cardiac and renal damage. The protective effect of KF6 against hypertension is attributed to its ability to modulate RAAS and intestinal microbiota.