Renal Fibrosis Mechanisms in Diabetic Kidney Disease

Diabetic kidney disease is characterised by progressive scarring of the renal interstitium and glomeruli, driven by persistent hyperglycaemia, haemodynamic shifts and low-grade inflammation. A central nexus in this process is the activation of transforming growth factor-β (TGF-β) signalling, which promotes deposition of extracellular matrix proteins such as collagens and fibronectin. Resident fibroblasts expand and become activated myofibroblasts, while epithelial and endothelial cells undergo transition programmes (EMT and EndMT) that further amplify matrix production. Metabolic reprogramming, including aberrant glycolysis and oxidative stress, contributes to profibrotic gene expression and cell death pathways such as ferroptosis. At the same time, dysregulated noncoding RNAs and secreted peptides influence transcriptional and post-transcriptional networks, sustaining fibrogenic signals. Epigenetic modifications and microRNA imbalances lock cells into a pro-scar phenotype. Together, these interconnected mechanisms culminate in loss of functional nephrons, progressive decline of glomerular filtration and eventual end-stage renal disease. Understanding the interplay between metabolic, inflammatory and epigenetic drivers of fibrosis has become pivotal in devising targeted therapies to halt or reverse tissue remodelling in diabetic kidneys.

Research from Nature Portfolio

A seminal study has revealed that the endogenous peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) orchestrates antifibrotic microRNA networks in diabetic kidneys. Restoration of key microRNA families countered the induction of dipeptidyl peptidase-4 and suppressed endothelial-to-mesenchymal transition, leading to marked reduction of extracellular matrix accumulation. This work illuminates a novel peptide-microRNA axis that may be harnessed to recalibrate profibrotic programmes in diabetic kidney disease.

Renal Fibrosis Mechanisms in Diabetic Kidney Disease publication trend

The graph below shows the total number of articles in renal fibrosis mechanisms in diabetic kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular matrix (ECM): A network of structural proteins and glycoproteins that support tissue architecture; excessive ECM deposition drives fibrosis.

Epithelial-to-mesenchymal transition (EMT): A cellular programme in which epithelial cells lose polarity and gain migratory, matrix-producing properties.

Endothelial-to-mesenchymal transition (EndMT): The process by which endothelial cells convert into mesenchymal, fibroblast-like cells contributing to matrix production.

Ferroptosis: Iron-dependent form of regulated cell death characterised by lipid peroxide accumulation and oxidative damage.

Fibroblast: A stromal cell type responsible for synthesis of ECM components during tissue repair and fibrosis.

Single-cell RNA sequencing (scRNA-seq): A high-resolution profiling technique that captures gene expression in individual cells, revealing heterogeneity and cell-state transitions.

References

1. Effect of Antifibrotic MicroRNAs Crosstalk on the Action of N-acetyl-seryl-aspartyl-lysyl-proline in Diabetes-related Kidney Fibrosis. Scientific Reports (2016).
2. The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism. Journal of Clinical Investigation (2024).
3. HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis. Cell Death & Disease (2024).
4. Multi‐organ single‐cell RNA sequencing in mice reveals early hyperglycemia responses that converge on fibroblast dysregulation. The FASEB Journal (2024).