Mitigating Lipotoxicity: A Potential Mechanism to Delay Chronic Kidney Disease Progression Using Current Pharmacological Therapies

Lipotoxicity, defined as the excessive accumulation of lipids in non-adipose tissues due to dysregulated lipid metabolism, is associated with several metabolic disorders, including insulin resistance, chronic kidney disease (CKD) and obesity. It contributes to renal injury through multiple interrelated mechanisms, including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, impaired autophagy, inflammation and oxidative stress, and ultimately causes damage to various renal cell types. Although current pharmacological therapies have demonstrated renoprotective effects, including renin-angiotensin system inhibitors (RASi), sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and non-steroidal mineralocorticoid receptor antagonists (NS-MRAs), their precise mechanisms of action are not fully understood. Lipid-lowering agents have also shown potential renal benefits in some studies, although their exact mechanisms are also still unclear. Emerging preclinical evidence indicates that these therapies may attenuate lipotoxicity via enhanced fatty acid oxidation (FAO), reduced cholesterol biosynthesis, decreased de novo lipogenesis, anti-inflammatory and antioxidant effects and improved mitochondrial function. These effects may represent key mechanisms in the attenuation of CKD progression. This review focuses on the proposed mechanisms by which these agents may alleviate lipotoxicity. It examines the cellular responses to lipid dysregulation and finally emphasises the need for further research to clarify these pathways and their clinical relevance.