Deletion of lymphotoxin-β receptor (LTβR) protects against acute kidney injury by PPARα pathway.

Background: Recent data has shown a considerable advancement in understanding the role of lymphotoxin-β receptor (LTβR) in inflammation. However, the functions and underlying mechanisms of LTβR in acute kidney injury (AKI) remain largely unknown.

Methods: AKI was induced in mice by renal ischemia-reperfusion (I/R). HK-2 cells and primary renal tubular epithelial cells (RTECs) were subjected to hypoxia/reoxygenation (H/R) injury. The effects of LTβR depletion were examined in mice, as well as primary RTECs. Bone marrow chimeric mice was generated to determine whether the involvement of LTβR expression by parenchymal cells or bone marrow derived cells contributes to renal injury during AKI. RNA sequencing techniques were employed to investigate the mechanism via which LTβR signaling provides protection against I/R-induced AKI RESULTS: LTβR expression was downregulated both in vivo and in vitro models of AKI. Moreover, depletion of LTβR decreased renal damage and inflammation in I/R-induced AKI. We also found that LTβR deficient mice engrafted with wild type bone marrow had significantly less tubular damage, implying that LTβR in renal parenchymal cells may play dominant role in I/R-induced AKI. RNA sequencing indicated that the protective effect of LTβR deletion was associated with activation of PPARα signaling. Furthermore, upregulation of PPARα was observed upon depletion of LTβR. PPARα inhibitor, GW6471, aggravated the tubular damage and inflammation in LTβR^-/- mice following I/R injury. Then we further demonstrated that LTβR depletion down-regulated non-canonical NF-κB and Bax/Bcl-2 apoptosis pathway through PPARα.

Conclusions: Our results suggested that the LTβR/PPARα axis may be a potential therapeutic target for the treatment of AKI.