Diabetes upregulates expression of the stress response protein Regulated in Development and DNA damage 1 (REDD1) in kidney podocytes, which increases renal cytokine and chemokine expression resulting in an exacerbated renal immune response. We observed that chronic REDD1 expression specifically in podocytes is required for sustained canonical nuclear factor kappa B (NF-κB) mediated proinflammatory signaling and immune cell infiltration in kidneys of diabetic mice. We also noted that podocyte-specific REDD1 deletion attenuated diabetes-induced NLRP3 associated pyroptosis in podocytes.

In diabetes, REDD1 is required for activation of the serine/threonine protein kinase Glycogen synthase kinase-3 beta (GSK-3β) in podocytes. Activation of this kinase is known to play a role in many biological processes including inflammation.  We demonstrated that REDD1-dependent GSK3 hyperactivity are associated with increased inflammation in the kidneys of diabetic mice. Notably, we demonstrated that REDD1 and GSK3 activity are both required for phosphorylation of the regulatory subunit of the upstream inhibitory κB kinase (NEMO) resulting in enhanced NF-κB activation and proinflammatory cytokine and chemokine expression.