AKI Initiates Hepatic Inflammation and Fibrogenic Signaling via Altered TLR4 Signaling Axis

Background: Increasing clinical studies demonstrate that acute kidney injury (AKI) is frequently accompanied by dysfunction of remote organs that contributes to the high mortality associated with AKI. In the current study, we evaluated the effects of ischemia-reperfusion AKI (IR-AKI) on liver injury. Methods: AKI was induced by bilateral clamping renal pedicles for 30 minutes at 37 °C, followed by 24 h of reperfusion. We evaluated liver serum biochemistry injury markers, histology, cytokines, inflammatory markers, fibrosis markers, and molecules involved in the TLR4 signaling pathway. Results: Compared with controls, the liver of AKI mice demonstrated significant hepatocellular injury: serum AST rose from 39.9 ± 5.1 U/L to 172.8 ± 62.8 U/L, and ALT from 21.3 ± 9.1 U/ L to 66.1 ± 13.6 U/ L. Histology analysis indicated steatosis changes with mixed inflammatory infiltrates. Cytokine array analysis showed significant increases in IL-1ra and B-lymphocyte chemoattractant (BLC). qRT-PCR confirmed up-regulation of chemokines MCP-1 and CXCL1, while immunohistochemistry analysis showed significantly increased CD68+ macrophages and a concomitant reduction in F4/80 staining. Fibrosis markers, including fibronectin, collagen I, and Notch3, were significantly induced, and Western blotting analysis showed increased phosphorylation of p53 and Notch3. Within the TLR4 signaling axis, mRNA levels of CD14 increased, MyD88 and MD-2 decreased, and TLR4 remained unchanged. Conclusion: Collectively, renal ischemia is sufficient to induce a rapid hepatic response, evidenced by inflammation, macrophage remodeling, and early fibrogenic signaling, partially mediated by dysregulated TLR4 co-receptors. These findings might be strengthening our understanding of kidney-liver crosstalk in AKI and may contribute to strategies to mitigate multi-organ injury in affected patients. Funding: NIDDK Support