Metabolic immune dysregulation in diabetic podocytopathy: mechanisms and therapeutic targets

Podocytes are terminally differentiated epithelial cells that contribute to the maintenance and normal function of the glomerular filtration barrier. Their foot processes interdigitate to form the slit diaphragm, built from marker proteins central to healthy glomerular filtration, including nephrin and podocin. Podocyte loss under chronic inflammation, hyperglycemia, and elevated intraglomerular pressure drives progressive glomerular scarring and irreversible renal decline, and podocyte injury lies at the core of diabetic kidney disease (DKD), the leading cause of end-stage renal disease worldwide.This Research Topic focuses on the immunological dimension of podocyte injury in type 2 diabetes mellitus (T2DM). It is explicitly distinct from classical autoimmune nephropathies — such as lupus nephritis, IgA nephropathy, or primary FSGS — where immune activation is the primary driver. The central question here is how the metabolic-immune crosstalk specific to the T2DM microenvironment primes and amplifies podocyte damage, and how that mechanistic understanding translates into actionable therapeutic targets.We welcome submissions addressing, but not limited to, the following themes:1. Cytokine networks and innate immune activation A complex cytokine milieu, including TNF-α, IL-1β, and IL-6, drives metabolically induced podocyte dysfunction through NF-κB and JAK/STAT signaling. The NLRP3 inflammasome becomes active in the hyperglycemic glomerular environment, and macrophages amplify the resulting inflammatory response. Emerging evidence linking cGAS-STING pathway activation to diabetic glomerular injury has recently been recognized.2. T cell dynamics in the diabetic glomerulus Th1, Th17, and regulatory T cell (Treg) subsets shape podocyte integrity in the context of T2DM. IL-17-producing Th17 cells activate NF-κB and MAPK pathways alongside IFN-γ signaling, while Tregs offer protection through IL-10.3. Oxidative-nitrosative stress: NOS and COX pathway cross-talk iNOS is upregulated in the diabetic kidney through NF-κB and STAT1, generating peroxynitrite-mediated lipid peroxidation, protein nitration, and caspase-9 activation, though its role here remains underexplored. COX-2-driven prostaglandin signaling interacts with TGF-β and reactive oxygen species, and the cross-talk between NOS and COX pathways amplifies podocyte apoptosis.4. Humoral immunity and complement activation B-cell activation generates autoantibodies and cytokines such as IL-6, which further overactivate JAK/STAT signaling in podocytes. Immune complex deposition and sublytic complement (C3/C5) activity, a potential target for agents such as ravulizumab, contribute further to injury in the diabetic glomerulus.5. Pharmacological targeting of immune-driven podocyte injury SGLT2 inhibitors offer renoprotection partly by attenuating NLRP3 inflammasome activation, while GLP-1 receptor agonists act via the cAMP/PKA and PI3K/Akt pathways. Additional therapeutic avenues include JAK inhibitors, anti-TGF-β and SMAD pathway agents, complement pathway inhibitors, dual endothelin/angiotensin blockade, and selective COX-2 inhibition.6. Metabolic-immune integration and emerging targets Lipid mediators, glycolytic metabolism, mitochondrial dysfunction, Adipokine signaling connects metabolic and immune dysfunction in the diabetic kidney. AMPK and PPAR pathway modulation, along with NADPH oxidase inhibitors and NOS modulators, target the resulting redox imbalance, and translational biomarkers are needed to link immune activity to glomerular outcomes in T2DM.Contributions from immunologists, biochemists, molecular biologists, nephrologists, and diabetologists are equally welcome. We particularly encourage work bridging pre-clinical models and clinical translation, as well as studies examining the intersection of metabolic dysfunction and immune regulation in the diabetic kidney.Submissions addressing diabetic kidney disease without a clear focus on the underlying immune or inflammatory mechanisms are outside the scope of this Research Topic.----Topic Editor Prof. Sharma’s has DSMB advisory roles for Sanofi and Cara Therapeutics Topic editors: Wissam H Faour, Sebastian Mertowski Source: https://www.frontiersin.org/research-topics/85806/metabolic-immune-dysregulation-in-diabetic-podocytopathy-mechanisms-and-therapeutic-targets