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Serine proteases, inhibitors and receptors in renal fibrosis
1University of Washington, Head, Division of Pediatric Nephrology, Seattle Children's Hospital and Research Institute, USA. allison.eddy@seattlechildrens.org
Abstract:
Chronic kidney disease (CKD) is estimated to affect one in eight adults. Their kidney function progressively deteriorates as inflammatory and fibrotic processes damage nephrons. New therapies to prevent renal functional decline must build on basic research studies that identify critical cellular and molecular mediators. Plasminogen activator inhibitor-1 (PAI-1), a potent fibrosis-promoting glycoprotein, is one promising candidate. Absent from normal kidneys, PAI-1 is frequently expressed in injured kidneys. Studies in genetically engineered mice have demonstrated its potency as a pro-fibrotic molecule. Somewhat surprising, its ability to inhibit serine protease activity does not appear to be its primary pro-fibrotic effect in CKD. Both tissue-type plasminogen activator and plasminogen deficiency significantly reduced renal fibrosis severity after ureteral obstruction, while genetic urokinase (uPA) deficiency had no effect. PAI-1 expression is associated with enhanced recruitment of key cellular effectors of renal fibrosis - interstitial macrophages and myofibroblasts. The ability of PAI-1 to promote cell migration involves interactions with the low-density lipoprotein receptor-associate protein-1 and also complex interactions with uPA bound to its receptor (uPAR) and several leukocyte and matrix integrins that associate with uPAR as co-receptors. uPAR is expressed by several cell types in damaged kidneys, and studies in uPAR-deficient mice have shown that its serves a protective role. uPAR mediates additional anti-fibrotic effects - it interacts with specific co-receptors to degrade PAI-1 and extracellular collagens, and soluble uPAR has leukocyte chemoattractant properties. Molecular pathways activated by serine proteases and their inhibitor, PAI-1, are promising targets for future anti-fibrotic therapeutic agents.
Insights
Plasminogen activator inhibitor-1 (PAI-1) drives kidney fibrosis by promoting cell migration, not protease inhibition. Targeting PAI-1 and urokinase plasminogen activator receptor (uPAR) pathways may offer new treatments for chronic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Chronic kidney disease (CKD) affects millions, characterized by progressive nephron damage from inflammation and fibrosis.
- Identifying key molecular mediators is crucial for developing therapies to prevent renal functional decline.
- Plasminogen activator inhibitor-1 (PAI-1) is a glycoprotein implicated in promoting fibrosis and is upregulated in injured kidneys.
Purpose of the Study:
- To investigate the role of PAI-1 and its associated pathways in the pathogenesis of renal fibrosis in CKD.
- To explore the pro-fibrotic mechanisms of PAI-1 beyond its serine protease inhibitory activity.
- To evaluate the potential of targeting PAI-1 and urokinase plasminogen activator receptor (uPAR) for anti-fibrotic therapies.
Main Methods:
- Studies utilizing genetically engineered mouse models with deficiencies in PAI-1, tissue-type plasminogen activator, plasminogen, and urokinase (uPA).
- Assessment of renal fibrosis severity following ureteral obstruction.
- Analysis of cellular and molecular interactions involving PAI-1, uPA, uPAR, and co-receptors (e.g., low-density lipoprotein receptor-associate protein-1, integrins).
Main Results:
- PAI-1 deficiency significantly reduced renal fibrosis, while uPA deficiency had no significant effect, suggesting PAI-1's pro-fibrotic role is independent of its protease inhibition.
- PAI-1 expression correlated with increased recruitment of interstitial macrophages and myofibroblasts.
- PAI-1 promotes cell migration via interactions with low-density lipoprotein receptor-associate protein-1 and uPAR-associated co-receptors.
- uPAR plays a protective role by mediating PAI-1 and collagen degradation and exhibiting chemoattractant properties for leukocytes.
Conclusions:
- PAI-1 is a critical mediator of renal fibrosis in CKD, acting primarily through cell migration pathways.
- The interaction between PAI-1, uPA, and uPAR is central to the development of kidney fibrosis.
- Targeting the molecular pathways involving PAI-1 and uPAR presents a promising therapeutic strategy for combating chronic kidney disease and preventing renal functional decline.
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