Mitogen-Activated Protein Kinase Signaling in Kidney Disease

Mitogen-activated protein kinase (MAPK) cascades are central to the regulation of cellular responses in the kidney, mediating signals from growth factors, cytokines and stress stimuli. The principal MAPK modules—extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and p38 kinases—coordinate cell survival, proliferation, apoptosis and extracellular matrix remodelling in glomerular and tubular compartments. Under pathological conditions such as diabetic nephropathy, acute kidney injury and chronic glomerulonephritis, persistent activation of JNK and p38 drives inflammation, epithelial–mesenchymal transition and tubulointerstitial fibrosis, while ERK dysregulation contributes to podocyte dysfunction. Upstream effectors including apoptosis signal-regulating kinase 1 (ASK1) and modulators of protein ubiquitination achieve fine control over MAPK activities. Preclinical studies employing selective inhibitors or genetic manipulation demonstrate that targeting key nodes of the MAPK network can attenuate renal injury and fibrogenesis, underscoring the translational promise of MAPK-based interventions in kidney disease.

Research from Nature Portfolio

Recent studies have identified a podocyte-specific deubiquitinating enzyme that modulates MAPK-driven inflammatory injury in diabetic kidney disease. Loss of this enzyme in podocytes heightened TAK1 phosphorylation, amplifying downstream JNK and p38 signals and exacerbating podocyte injury in both type 1 and type 2 diabetic mouse models. Conversely, gene therapy–mediated restoration of enzyme expression reduced TAK1 activity, suppressed MAPK-mediated inflammation and ameliorated proteinuria. These findings reveal a deubiquitinase–TAK1 axis as a novel regulator of MAPK signalling in podocyte health and pave the way for targeted therapies that preserve glomerular function in diabetic nephropathy.

Mitogen-Activated Protein Kinase Signaling in Kidney Disease publication trend

The graph below shows the total number of articles in mitogen-activated protein kinase signaling in kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Mitogen-activated protein kinase (MAPK): A family of protein kinases including ERK, JNK and p38 that transduce extracellular signals to regulate cell fate and gene expression.

Podocyte: Specialized epithelial cell in the kidney glomerulus that forms part of the filtration barrier and maintains capillary wall integrity.

Deubiquitination: The enzymatic removal of ubiquitin moieties from proteins, modulating their stability and activity.

Transforming growth factor-β-activated kinase 1 (TAK1): An upstream kinase that activates JNK and p38 pathways in response to pro-inflammatory signals.

Tubulointerstitial fibrosis (TIF): Pathological accumulation of extracellular matrix in the renal interstitium leading to impaired tubular function.

Senolytic: An agent that selectively induces death of senescent cells to alleviate age- or stress-related pathologies.

Senostatic: A compound that suppresses the senescence-associated secretory phenotype without killing senescent cells.

Dual-specificity phosphatase 6 (DUSP6): A phosphatase that deactivates ERK by dephosphorylation, thereby attenuating MAPK signalling.

Apoptosis signal-regulating kinase 1 (ASK1): A MAPK kinase kinase that responds to oxidative stress to initiate p38 and JNK activation.

References

1. Podocyte OTUD5 alleviates diabetic kidney disease through deubiquitinating TAK1 and reducing podocyte inflammation and injury. Nature Communications (2024).
2. Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury. Clinical Science (2024).
3. Minichromosome maintenance 6 protects against renal fibrogenesis by regulating DUSP6-mediated ERK/GSK-3β/Snail1 signaling. iScience (2023).
4. ASK1 inhibitor treatment suppresses p38/JNK signalling with reduced kidney inflammation and fibrosis in rat crescentic glomerulonephritis. Journal of Cellular and Molecular Medicine (2018).