2026· Journal of Medical Biochemistry· pp. 157-157· 0 citations· 60 references
TL;DR
Clinically, circulating and urinary GDF15 levels correlate with disease severity and independently predict renal function decline, suggesting utility in both early diagnosis and prognostic stratification and its potential role as a pharmacodynamic marker responsive to interventions such as metformin and SGLT2 inhibitors is supported.
Abstract
Background: Diabetic kidney disease (DKD) remains a
major cause of end-stage renal disease worldwide, yet
current clinical biomarkers such as albuminuria and estimated glomerular filtration rate lack sufficient sensitivity
to detect early renal injury or predict individual disease
trajectories. Growth differentiation factor 15 (GDF15), a
stress-inducible cytokine belonging to the transforming
growth factor-b superfamily, has emerged as a promising
molecular link between metabolic stress, inflammation,
mitochondrial dysfunction, and renal injury in diabetes.
This review systematically synthesizes current experimental and clinical evidence on the role of GDF15 in
DKD, with emphasis on its mechanistic involvement in
renal pathophysiology and its translational potential as
a biomarker and therapeutic target. Evidence from preclinical models and human studies indicates that GDF15
is upregulated in diabetic kidneys, particularly in tubular
epithelial cells, in response to hyperglycemia-induced
oxidative stress and mitochondrial dysfunction. Mechanistically, GDF15 modulates key pathogenic pathways in
DKD, including NF-kB–mediated inflammation, NLRP3
inflammasome activation, macrophage polarization,
TGF-b/Smad-driven fibrogenesis, and autophagy regulation through PI3K/Akt and AMPK signaling. Clinically, circulating and urinary GDF15 levels correlate with disease
severity and independently predict renal function decline,
suggesting utility in both early diagnosis and prognostic stratification. In addition, emerging evidence supports its
potential role as a pharmacodynamic marker responsive
to interventions such as metformin and SGLT2 inhibitors.
However, its context-dependent biological effects, lack
of assay standardization, and confounding elevation in
systemic diseases remain key challenges. Overall, GDF15
represents a central stress-integrating mediator in DKD
pathogenesis and a promising candidate for precision
nephrology, warranting further validation in longitudinal
multi-omics and interventional studies.
INTRODUCTION
Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease, and podocyte injury is a pivotal driver of albuminuria, glomerulosclerosis, and progressive loss of kidney function.
METHODS
A targeted narrative search of PubMed/MEDLINE, Scopus, and Web of Science was performed, primarily covering 2015-2025 and supplemented by seminal earlier studies. Inclusion criteria prioritized human studies, randomized and translational studies, and mechanistic work directly addressing podocyte injury or podocyte-relevant therapeutic effects in DKD. Studies with limited mechanistic or translational relevance were excluded or deprioritized.
RESULTS
Diabetic metabolic and hemodynamic stress activates AGE/PKC/RAAS signaling and downstream TGF-β/Smad, NF-κB, PI3K/Akt/mTOR, TRPC6-Ca2+, and mitochondrial stress pathways. These pathways converge on slit diaphragm disruption, actin cytoskeletal remodeling, impaired autophagy, ER stress, apoptosis, detachment, and progressive podocyte depletion. Current standard-of-care therapies, including RAAS blockade, SGLT2 inhibitors, GLP-1 receptor agonists, and finerenone, provide partial podocyte-relevant renoprotection, whereas endothelin receptor antagonists, anti-TGF-β/CTGF approaches, JAK/STAT inhibitors, TRPC6 blockade, redox-targeted therapies, RNA-based strategies, and extracellular vesicle approaches remain at different stages of clinical readiness.
DISCUSSION
The available evidence supports a layered model in which systemic metabolic and hemodynamic therapies reduce upstream stress, while emerging podocyte-directed strategies aim to stabilize cytoskeletal, slit diaphragm, inflammatory, fibrotic, calcium, and organelle-stress pathways. Combination therapy is biologically plausible but should be guided by albuminuria, eGFR, cardiometabolic phenotype, tolerability, and validated podocyte-related biomarkers.
CONCLUSION
A podocyte-centered framework that links mechanisms, biomarkers, evidence tiering, and patient stratification may improve translation of targeted and combination strategies. However, clinical implementation requires stronger biomarker validation, optimized human-relevant models, and long-term safety and outcome data.
The cellular and molecular mechanisms of EndMT relevant to CKD are summarized, key regulatory pathways and pathway crosstalk are highlighted, and emerging pharmacological approaches to limit EndMT, preserve microvascular integrity, and attenuate renal fibrogenesis are discussed.
Abdul Khan, Pratheesh D. Mankuzhy, L. Thomas et al.· Kidney & Blood Pressure Rese...· 0 citations
This review uses Tangshen formula, a classic traditional Chinese medicine (TCM) for DKD, to detail TCM's protective mechanisms and concisely summarizes the DKD-related preclinical progress of other TCMs over 5 years.
Li Jiang, Shuang Guo, Yufei Zhang et al.· Seminars in Nephrology· 0 citations
Diabetic nephropathy (DN) is a diabetic complication that leads to the progressive deterioration of kidney function. Oxidative stress and inflammation play crucial roles in the pathogenesis of DN. Oral hypoglycemic agents such as sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors show renal protective effects and help in slowing the progression of the disease. Emerging therapeutic targets, including phosphodiesterase inhibitors, Vitamin D analogues, and others, are being explored for treating DN. The development of newer biomarkers needs more attention and clinical acceptance for the timely diagnosis and management of DN. The present review attempts to discuss the different stages of DN, the pathophysiological mechanisms involved in DN development and progression, and potential biomarkers (Neutrophil Gelatinase-Associated Lipocalin, β2-microglobulin, Kidney Injury Molecule-1, Serum homocysteine, β-trace protein, Angiotensinogen, Osteopontin, Urinary exosomes, MicroRNAs) and therapeutic approaches for the effective management of DN.
Kuldip Vyas, Abu Sufiyan Chhipa, Ayush chauhan et al.· Discover Molecules· 0 citations
This review systematically examines the mechanisms of metabolic reprogramming in different renal cell types and highlights their contribution to renal injury, highlighting the ability of natural products to confer renal protection by modulating key regulatory nodes of metabolic reprogramming.
Wenru Wang, Han Zhu, Keqin Zhao et al.· Journal of Translational Int...· 0 citations
SIGNIFICANCE
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease worldwide. Its burden continues to increase despite advances in glycemic and blood pressure control. This persistent risk highlights the need for therapeutic strategies that address injury-amplifying mechanisms beyond conventional metabolic and hemodynamic pathways. Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a contributor to renal injury in DKD. However, its precise role in human disease is incompletely defined.
RECENT ADVANCES
Ferroptosis is closely linked to lipid peroxidation-derived danger signals that promote innate immune activation, including M1 macrophage polarization, neutrophil infiltration, dendritic-cell maturation, TLR4 signaling, and NLRP3 inflammasome activation. Ferroptotic cells release damage-associated molecular patterns, including HMGB1, which activate inflammatory cascades. In turn, inflammatory cytokines disrupt iron homeostasis, increase oxidative stress, and further sensitize renal cells to ferroptosis, forming a self-amplifying ferroptosis-immunity feedback loop.
CRITICAL ISSUES
Candidate biomarkers, including GPX4 depletion, ACSL4 expression, lipid peroxidation products, interleukin-18, and NLRP3 activation, may support earlier risk assessment and patient stratification. However, clinical validation is limited, and standardized biomarker thresholds, longitudinal human data, renal-cell-specific targeting, and long-term safety data are still lacking.
FUTURE DIRECTIONS
Therapeutic strategies under investigation include ferroptosis inhibitors, iron chelators, GPX4-directed approaches, TLR4/NLRP3-targeted immunomodulators, kidney-targeted nanoparticles, and CRISPR-based modulation of ferroptosis regulators. Multiomics profiling and artificial intelligence may further support rational combination therapies. Targeting the ferroptosis-immunity axis alongside optimal glycemic control may provide a complementary mechanism-based strategy to delay DKD progression. Antioxid. Redox Signal. 00, 000-000.
Wen Zhang, Su-Mei Xu, Zhi-Jian Cao et al.· Antioxidants and Redox Signa...· 0 citations
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