LXR/mTOR Signaling Axis Modulation: A Novel Approach for Regulating Autophagy in Diabetic Kidney Disease

Background: Podocyte damage is crucial in diabetic kidney disease (DKD) pathogenesis. As podocytes have limited division capacity, autophagy is essential for their repair and homeostasis. Autophagy is described to be deregulated in diabetes. Yet, the underlying mechanism is still unclear. The mTOR complexes and oxidative stress have emerged as potential key players in mediating diabetes-induced autophagy imbalance. The role of the Liver-X-Receptor (LXR) in DKD has been mildly highlighted, but its role in autophagy and its crosstalk with key mechanistic pathways in DKD remains unclear. In this study, we investigate the role of the LXR/mTOR axis in autophagy and its possible link to podocyte injury in type 1(T1DM) and type 2 diabetes mellitus (T2DM). Methods: An immortalized human podocyte cell line was used for our in vitro studies. Human podocytes were transfected with siRNA against LXR-α/β, Raptor, Rictor, or LC3B. For the in vivo model, T1DM and T2DM were experimentally induced in mice. Mice were treated with LXR activator T0 or DMHCA, mTORC1 inhibitor Rapamycin, or the mTORC2 inhibitor JR-AB2-011. In parallel experiments, control mice were treated with autophagy inhibitor Hydroxychloroquine (HCQ). We assessed functional, histological, biochemical, and molecular parameters of the kidneys. Results: Our results show that LXR activation attenuates podocyte and renal injury by inhibiting Nox4-dependent reactive oxygen species production and restoring autophagy. Mechanistically, this effect is mediated through the downregulation of both mTORC1 and mTORC2 activity. Interestingly, inactivation of either mTORC1 or mTORC2 pathways, both in vitro and in vivo, recapitulates the protective effects observed upon LXR activation, without altering the LXR pathway itself. Furthermore, our findings underscore the clinical relevance of autophagy signaling in DKD, as treatment with HCQ in control mice mimics the renal alterations seen in diabetes. Importantly, our study identifies mTORC2, in addition to mTORC1, as a key regulator of autophagy in the context of DKD. Conclusion: This study highlights the interplay between LXR inactivation and mTORC1 activation, leading to autophagy dysregulation in DKD. Additionally, the activation of mTORC2 emerges as a critical factor in this process.