Background: Hypertension is a major cause for cardiovascular and renal diseases. The Z. spina-christi has a rich source of ethnomedicinal background and diverse bioactive compounds suggesting that its associated endophytic fungi may characterize a valuable source of novel therapeutic metabolite with potential applications in cardiovascular and renal diseases. Objectives: This research aims to investigate the antihypertensive and nephroprotective potential through endophytic fungus ZS1 isolated from Ziziphus spina-christiin-vitro, in-vivo and Renin-angiotensin converting enzyme inhibitory assays. Methods: The ZS1 strain was identified by Sanger sequencing and phylogenetic assay (NCBI, Mega-X). Ethyl acetate extract of the fungal culture was prepared and evaluated for antihypertensive activity in high-salt-induced hypertensive Wistar rats, with blood pressure, biochemical parameters, renin and ACE inhibition and kidney histopathology. Acute toxicity testing was conducted according to OECD guideline 425. Results: The fungal strain ZS1 was classified as Aspergillus aculeatus with GenBank Accession No. PQ192175. The extract showed dose-dependent reduction in systolic and diastolic blood pressure, with 200 mg/kg dose showing results comparable to those of captopril (30 mg/kg). In-vitro renin and ACE inhibition demonstrated dual inhibitory action, supporting modulation of RAS pathway as a potential mechanism of action. GC-MS analysis identified several bioactive compounds such as oleic acid, n-hexadecanoic acid, octadecanoic acid, and thymol, which are well known for their antihypertensive, anti-inflammatory, and antioxidant properties. Histopathological analysis of renal tissues revealed significant restoration of normal architecture, particularly at higher dose, officiating a significant nephroprotective activity. Conclusion: These findings suggested that Aspergillus aculeatus represents a promising natural source of antihypertensive and nephroprotective agents. Further studies focusing on isolation of active compounds and elucidation of their molecular mechanisms are required to explore their therapeutic and pharmaceutical potential.
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