Exogenous spexin aggravates renal ischemia reperfusion injury and triggers toxicity in healthy kidneys

Chronic subcutaneous spexin (50 µg kg⁻¹ day⁻¹ for 4 weeks) not only amplifies ischaemia–reperfusion-induced AKI in male BALB/c mice but also provokes overt nephrotoxicity in otherwise healthy kidneys, overturning the peptide’s previously advertised renoprotective image and linking the damage to sustained Wnt/β-catenin signalling, systemic inflammation and early fibrogenesis. Six hours after bilateral 30-min renal ischaemia, animals that had received spexin exhibited higher serum creatinine and KIM-1 than vehicle-treated IRI controls, while spexin-alone mice already showed elevated SCr, moderate tubular necrosis, cast formation and glomerular sclerosis, proving an intrinsic renal insult independent of ischaemia. Histological injury scores and Masson-trichrome fibrosis indices rose in parallel; α-SMA and fibronectin accumulated in spexin-exposed kidneys even without IRI, heralding prompt profibrotic priming.

Molecular profiling revealed that spexin broadly ignites the Wnt cascade: renal mRNA and protein of Wnt-4, Wnt-7b and β-catenin increased 2–3-fold over baseline in healthy spexin mice and were further amplified when IRI was superimposed, indicating synergistic pathway hyper-activation. Down-stream, pro-apoptotic p53 and Bax were up-regulated while anti-apoptotic Bcl-2 protein remained unchanged, tilting the balance toward cell death. Simultaneously, tissue levels of IFN-γ, IL-18, MCP-1, MIP-2, TNF-α and iNOS surged above IRI-only values, documenting a spexin-driven hyper-inflammatory milieu that exceeds the cytokine burst triggered by reperfusion alone.

The study challenges earlier reports that acute spexin exerts antioxidant, anti-inflammatory and metabolic benefits, and underscores context-dependency: chronic exposure in normal kidneys converts the peptide into a pro-inflammatory, pro-fibrotic stimulus that amplifies AKI-to-CKD transition. Limitations—single 6-h observation, absence of Wnt-pathway blockade, and lack of dose–response—are acknowledged, yet the data provide the first warning that long-term spexin supplementation may endanger rather than protect renal parenchyma, urging cautious re-evaluation of its therapeutic potential in patients with underlying kidney vulnerability.