Heparin prevents AKI to CKD transition via HDAC1-mediated anti-inflammatory effect independent from its anticoagulant properties

Heparin or chemically modified variant devoid of anticoagulant activity (N-Acetyl heparin sodium salt) was administered subcutaneously. Histological analyses, including H&E staining, Masson’s trichrome staining, immunofluorescence, and immunoblotting, were employed to assess renal tubular cell injury, interstitial fibrosis and inflammatory cell infiltration in the kidneys. RNA sequencing of murine kidney cortex tissues was performed to elucidate the mechanistic actions of heparin. Additionally, drug affinity responsive target stability (DARTS) assays and co-immunoprecipitation were conducted to explore the interaction between HDAC1 and heparin. Key findings: We found that low-dose heparin treatment significantly mitigates the AKI to CKD transition, primarily through the suppression of inflammation responses. Mechanistically, heparin binds to HDAC1 in renal tubular epithelial cells, reducing the acetylation of p65，which in turn downregulates the expression of inflammatory factors. Notably, this anti-inflammatory effect of heparin is independent of its anticoagulant activity, as the interaction between heparin and HDAC1 is unrelated to its anticoagulant domain. Furthermore, the chemically modified variant of heparin (N-Acetyl heparin sodium salt), lacking anticoagulant properties, demonstrated a similar protective effect. Significance: Our findings suggest that low-dose heparin, along with its non-anticoagulant derivatives, holds potential as a novel therapeutic approach to attenuate the progression from AKI to CKD.