Ambroxol mitigates renal ischemia/reperfusion-induced cardiac and renal injury via Nrf2/HO-1 activation and TLR4 pathway inhibition.

Background: Ambroxol is a mucokinetic drug with antioxidant and anti-inflammatory properties. Renal ischemia/reperfusion (IR) is the cause of acute kidney injury that usually occurs with other comorbidities.

Objectives: To explore ambroxol for repurposing against renal IR-induced cardio-renal injury.

Methods: Sprague-Dawley rats were assigned into: Sham group (Group I), untreated renal IR group (Group II), and ambroxol-pretreated group (Group III). Cardiac injury parameters, histopathology, and oxidative and antioxidant status, plus signaling molecules related to hypoxia, inflammation, mitochondrial dysfunction, and apoptosis were evaluated.

Key findings: Ambroxol administration significantly (P < .001) improved the IR-deteriorated cardiac biomarkers and histopathology and up-regulated the Nrf2/HO-1 pathway to increase antioxidant capacity. The cardio-renal expression of hypoxia-inducible factor (HIF)-1α was significantly (P < .001) attenuated by ambroxol. Ambroxol also attenuated inflammation by significant (P < .001) down-regulation of TLR4, p38 mitogen-activated protein kinase, nuclear factor kappa B, and nod-like receptor protein 3 expression while decreasing IL-1β and TNF-α secretion. Moreover, ambroxol significantly (P < .001) ameliorated mitochondrial dysfunction and apoptosis. Statistical results revealed positive correlations between the expression of TLR4 and HIF-1 and between TLR4 and dynamin-related protein 1.

Conclusions: Ambroxol's cardio-renal protecting potential was elicited by inhibiting oxidative stress, inflammation, and mitochondrial dysfunction through activating the Nrf2/HO-1 pathway and inhibiting multiple TLR4-interconnected signaling pathways, thus affording a theoretical base for ambroxol's clinical use in renal IR-induced injuries.