New Perspectives on Obesity-Associated Nephropathy from Pathophysiology to Therapeutics: Revealing the Promise of GLP-1 RA Therapy

Linan Ren,1,2 Feng Ju,3 Siyuan Liu,1,2 Yunjia Cai,1,2 Xiaokun Gang,1 Guixia Wang1 1Department of Endocrinology and Metabolism, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China; 2Institute of Translational Medicine, First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China; 3Department of Orthopedics, Yuci District People’s Hospital, Yuci, Shanxi, 030600, People’s Republic of ChinaCorrespondence: Xiaokun Gang; Guixia Wang, Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin Province, 130021, People’s Republic of China, Email [email protected]; [email protected]: Obesity represents a substantial risk factor for a multitude of metabolic disorders, which seriously threatens human life and health. As the global obesity epidemic intensifies, obesity-related nephropathy (ORN) has attracted great attention. ORN arises from both physical/mechanical and non-physical insults to the glomerular and tubular structures precipitated by obesity, culminating in structural impairments and functional aberrations within the kidneys. Physical injury factors include changes in renal hemodynamics, renal compression, and mechanical stretching of podocytes. Non-physical injury factors include overactivation of the RAAS system, insulin resistance, lipotoxicity, inflammation, and dysregulation of bile acid metabolism. Exploring molecules that target modulation of physical or nonphysical injury factors is a potential approach to ORN treatment. ORN is characterized clinically by microproteinuria and pathologically by glomerulomegaly, which is atypical and makes early diagnosis difficult. Investigating early diagnostic markers for ORN thus emerges as a critical direction for future research. Additionally, there is no specific drug for ORN in clinical treatment, which mainly focuses on weight reduction, mitigating proteinuria, and preserving renal function. In our review, we delineate a progressive therapeutic approach involving enhancements in lifestyle, pharmacotherapy, and bariatric surgery. Our emphasis underscores glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as poised to emerge as pivotal therapeutic modalities for ORN in forthcoming clinical avenues. Keywords: Obesity-related nephropathy, pathophysiology, diagnostics, therapeutics