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

## TL;DR

This study identifies a new pathway involving TrkA and CDK5 in diabetic kidney disease, suggesting TrkA inhibition could be a promising treatment.

## Contribution

The study reveals a novel TrkA-p35/CDK5 axis linking neurotrophic signaling to renal inflammation in DKD.

## Key findings

- TrkA inhibition reduces phosphorylation and inflammation in diabetic kidney disease models.
- Phosphorylation of TrkA at Tyr490 activates the ERK/EGR1 pathway, contributing to podocyte injury.
- NGFR is upregulated in db/db mice, and TrkA overexpression worsens high-glucose-induced damage.

## Abstract

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.

The renal transcriptional profiles were evaluated in db/db mice and controls. High glucose (HG) stimulation was used to induce an in vitro model of podocyte injury. The therapeutic effects of the TrkA inhibitor GW441756 were evaluated in both DKD model mice and HG-stimulated podocytes.

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.

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.