The Angiotensin II Receptor Antagonist Losartan Impairs Female Fertility in Rats: Potential Mediating Role of microRNA-129-1-3p

Angiotensin II receptor antagonists (ARBs), such as losartan, are widely prescribed for the management of hypertension and various cardiovascular disorders. However, their potential effects on female fertility remain largely unexplored. This study aimed to investigate the impact of losartan on ovarian function and fertility in female Wistar albino rats. Rats were orally administered low (0.7 mg/kg) and high (1.4 mg/kg) doses of losartan daily for 1 month. Following the treatment period, ovaries were collected, weighed, fixed, and subjected to comprehensive analysis for markers associated with folliculogenesis and steroidogenesis. Specifically, histopathological, immunofluorescence, RT-PCR, and in silico analyses were performed on ovarian tissues. The results demonstrated a significant reduction in fertility rates, accompanied by notable alterations in follicular development and ovarian histoarchitecture. Furthermore, losartan treatment led to a decreased expression of Cyp19 while concurrently increasing the expression of Estrogen receptor genes, Esr1 and Esr2, and insulin-like growth factor 1 (Igf1). Crucially, the mRNA expression levels of anti-Müllerian hormone (Amh), a reliable indicator of ovarian reserve, were disrupted. Biochemical analyses revealed reduced glutathione levels and increased malondialdehyde levels, further indicating oxidative stress and ovarian cellular damage, consistent with the observed histopathological findings. In silico docking studies provided insights into potential molecular mechanisms, revealing interactions between losartan, microRNA-129-1-3p, and the mRNA expression levels of Esr1 and Esr2, which may contribute to the observed molecular changes. These findings collectively underscore the detrimental impact of losartan on ovarian health and highlight the urgent need for further comprehensive research into its effects on female reproductive health.