Protease-Activated Receptor Signaling in Chronic Kidney Disease

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors activated by proteolytic cleavage, notably by coagulation proteases such as thrombin and factor Xa. In chronic kidney disease (CKD), aberrant activation of PAR1 and PAR2 on renal cell types—including tubular epithelial cells, mesangial cells and endothelial cells—drives inflammation, fibrosis and functional decline. Engagement of PAR1 on mesangial cells promotes proliferation and extracellular matrix deposition, whereas PAR2 activation in proximal tubules enhances secretion of proinflammatory cytokines and fibrogenic mediators. These receptors signal through classical pathways involving NF-κB, MAPKs and Smad transcription factors, and they cross-talk with transforming growth factor-β and epidermal growth factor receptor cascades. The net result is tubulointerstitial inflammation, epithelial-to-mesenchymal transition and progressive fibrotic remodelling. Preclinical studies highlight the global significance of PAR signalling in diabetic nephropathy, obstructive nephropathy and injury-to-CKD transition, revealing opportunities for therapeutic intervention with receptor antagonists or coagulation-targeted agents to slow CKD progression and reduce end-stage renal disease burden.

Research from Nature Portfolio

Genetic ablation of PAR1 in a diabetic mouse model demonstrated a marked reduction in proteinuria, mesangial expansion and tubular atrophy despite equivalent hyperglycaemia, establishing PAR1 as a key driver of diabetic nephropathy. PAR1-deficient mice exhibited lower levels of fibronectin and collagen IV, underscoring the receptor’s role in matrix accumulation. In a complementary approach, therapeutic inhibition of factor Xa with an oral anticoagulant attenuated renal tubulointerstitial fibrosis in an obstructive nephropathy model. Treatment reduced expression of both PAR1 and PAR2 in kidney tissue, limited macrophage infiltration and downregulated profibrotic cytokines, suggesting that targeting upstream coagulation proteases can modulate PAR-dependent kidney injury.

Protease-Activated Receptor Signaling in Chronic Kidney Disease publication trend

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

Technical terms

Protease-activated receptor (PAR): A class of G-protein-coupled receptors activated when specific extracellular proteases cleave their N-terminal domain, revealing a tethered ligand.

G-protein-coupled receptor (GPCR): A membrane receptor that transduces extracellular signals into intracellular responses via heterotrimeric G proteins.

Tubulointerstitial fibrosis: Pathological accumulation of extracellular matrix in the renal interstitium and tubular compartments leading to scarring and loss of kidney function.

Epithelial-to-mesenchymal transition (EMT): A process by which epithelial cells acquire mesenchymal characteristics, contributing to fibrotic tissue remodelling.

Biased antagonist: A ligand that selectively inhibits particular signalling pathways downstream of a receptor, preserving other beneficial responses.

References

1. PAR2 activation on human tubular epithelial cells engages converging signaling pathways to induce an inflammatory and fibrotic milieu. Frontiers in Pharmacology (2024).
2. Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis*. Journal of Biological Chemistry (2013).
3. Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice. Scientific Reports (2016).
4. Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis. Scientific Reports (2018).
5. The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis.. Clinical Science (2020).
6. Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy. Journal of Cellular and Molecular Medicine (2018).