Unveiling the TrkA-p35/CDK5 axis: a novel therapeutic target in diabetic kidney disease

Objective: To investigate the potential crosstalk between TrkA, the high-affinity nerve growth factor receptor (NGFR), and cyclin-dependent kinase 5 (CDK5) in the pathogenesis of diabetic kidney disease (DKD). Furthermore, this study aims to evaluate the therapeutic potential of targeting TrkA in DKD. Methods: model of podocyte injury. The therapeutic effects of the TrkA inhibitor GW441756 were evaluated in both DKD model mice and HG-stimulated podocytes. Results: RNA sequencing detected NGFR upregulation in db/db mice. Phosphorylation of TrkA (Tyr490) increased in HG-stimulated podocytes, and TrkA overexpression aggravated HG-induced injury. Mechanistically, TrkA activation functionally links to CDK5 in the pathogenesis of DKD. Specifically, phosphorylation of TrkA at Tyr490 triggers the activation of the downstream ERK/EGR1 pathway. The accumulation of p35 activated CDK5, resulting in an inflammation-mediated podocyte injury. The TrkA inhibitor reduced its phosphorylation and attenuated downstream inflammation. Conclusion: Our findings suggest a TrkA-p35/CDK5 axis contributes to podocyte inflammation and injury, connecting neurotrophic signalling and renal metabolic inflammation through a novel mechanism. This work indicates that TrkA represents a potential therapeutic target for DKD therapy.