Modulating the LXR-GDF15-NETosis Pathway to Attenuate Diabetic Kidney Disease

Abstract

Background: Diabetic Kidney Disease (DKD) remains a leading cause of end-stage renal disease (ESRD), driven by multifactorial mechanisms such as oxidative stress, inflammation, and programmed cell death. Emerging research implicates NETosis, a form of neutrophil cell death involving the release of neutrophil extracellular traps (NETs), in amplifying kidney injury. Growth Differentiation Factor 15 (GDF15), a stress-responsive cytokine, and Liver X Receptors (LXRs), nuclear receptors involved in lipid metabolism and inflammation, have been independently linked to DKD progression. However, the mechanistic interplay between LXRs and GDF15 and their collective impact on NETosis in DKD is not well defined.

Hypothesis: We hypothesize that LXR activation suppresses GDF15 expression, thereby mitigating oxidative stress, inhibiting NETosis, and ultimately protecting against DKD.

Methods: Type 2 diabetes mellitus (T2DM) was induced in C57BL/6J mice using a High Fat Diet/STZ model. Mice were divided into three groups: control, untreated T2DM, and T2DM treated with the LXR agonist DMHCA for 12 weeks. Renal function, histological changes, oxidative stress markers, GDF15 expression, and NETosis markers were assessed through biochemical, molecular, and histological analyses.

Results: Diabetes downregulated renal LXRα/β expression and increased cholesterol accumulation, oxidative stress, GDF15 levels, and NETosis markers (MPO and NE). LXR activation restored LXR signaling, decreased renal cholesterol levels, reduced GDF15 expression, and inhibited NOX4-dependent ROS production. This cascade significantly reduced NETosis and improved renal morphology and function, independently of glycemic control.

Conclusion: Pharmacological activation of LXRs attenuates DKD progression through suppression of the GDF15-NOX4-NETosis axis. This study identifies the LXR-GDF15-NETosis pathway as a novel mechanistic and therapeutic target in the management of DKD.