Diabetic Kidney Disease: Disease Progression Driven by Positive Feedback Loops and Therapeutic Strategies Targeting Pathogenic Pathways

Gaozhi P Mo,1,* Yao Zhu,1,* Yue You,1 Hui Chen,1 Jiahao Zhang,1 Bunhav Ku,1 Haichuan Yu,1 Zhiyong Peng1,2 1Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Hubei Clinical Research Center for Critical Care Medicine, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyong Peng, Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, Hubei, 430071, People’s Republic of China, Tel +86-27-6781-2928, Fax +86-27-6781-2892, Email [email protected] Haichuan Yu, Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuchang District, Wuhan, Hubei, 430071, People’s Republic of China, Tel +86-27-6781-2928, Fax +86-27-6781-2892, Email [email protected]: Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, with its pathogenesis intricately regulated by dynamic feedback mechanisms. This comprehensive review systematically analyzes the hierarchical feedback networks driving DKD progression, spanning from systemic interactions to molecular cross-talks. We reveal that self-amplifying positive feedback loops dominate the disease process, manifested through three key dimensions: (1) The systemic triad of hyperglycemia-hypertension-proteinuria establishes a vicious cycle accelerating renal dysfunction; (2) Cellular homeostasis collapse through cross-amplified cell death modalities (apoptosis, pyroptosis, ferroptosis) and cell cycle dysregulation; (3) Molecular cascades centered on AGE/RAGE signaling that fuel chronic inflammation and fibrotic transformation. Collectively, these form a major positive feedback loop where PKC activation, oxidative stress propagation, and TGF-β-mediated fibrosis induced by hyperglycemia lead to progressive renal deterioration and fibrosis. Therapeutically, we propose a dual intervention strategy targeting both the acute phase through AGE/RAGE axis inhibition, coupled with chronic phase via precision modulation of fibrotic pathways. These findings redefine DKD progression as a self-reinforcing network disorder, providing a roadmap for developing multi-target therapies that disrupt pathological feedback loops while preserving renal repair mechanisms.Plain Language Summary: Positive feedback exists in diabetic kidney disease to drive disease progression.High glucose induced cell death and cell cycle disruption alter the cellular homeostasis.Fibrosis and inflammatory response, cell adhesion, angiogenesis, and thrombogenesis promote each other.The gradual development of the disease may lead to renal fibrosis and even end-stage renal disease.Diabetic kidney disease can be treated through intervention in the positive feedback process.Keywords: diabetic kidney disease, feedback, hyperglycemia, advanced glycation end products, fibrosis, treatment