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Updated: Oct 20, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Coagulation, Protease-Activated Receptors, and Diabetic Kidney Disease: Lessons from eNOS-Deficient Mice
Yuji Oe1, Mariko Miyazaki1, Nobuyuki Takahashi2
1Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine.
Abstract:
Endothelial nitric oxide synthase (eNOS) dysfunction is known to exacerbate the progression and prognosis of diabetic kidney disease (DKD). One of the mechanisms through which this is achieved is that low eNOS levels are associated with hypercoagulability, which promotes kidney injury. In the extrinsic coagulation cascade, the tissue factor (factor III) and downstream coagulation factors, such as active factor X (FXa), exacerbate inflammation through activation of the protease-activated receptors (PARs). Recently, it has been shown that the lack of or reduced eNOS expression in diabetic mice, as a model of advanced DKD, increases renal tissue factor levels and PAR1 and 2 expression in their kidneys. Furthermore, pharmaceutical inhibition or genetic deletion of coagulation factors or PARs ameliorated inflammation in DKD in mice lacking eNOS. In this review, we summarize the relationship between eNOS, coagulation, and PARs and propose a novel therapeutic option for the management of patients with DKD.
Insights
Endothelial nitric oxide synthase (eNOS) dysfunction worsens diabetic kidney disease (DKD) by increasing blood clotting and inflammation. Targeting coagulation factors and protease-activated receptors (PARs) may offer new treatments for DKD.
Area of Science:
- Nephrology
- Vascular Biology
- Coagulation Science
Background:
- Endothelial nitric oxide synthase (eNOS) dysfunction is a key factor in diabetic kidney disease (DKD) progression.
- Reduced eNOS levels are linked to hypercoagulability, promoting kidney injury in DKD.
- The extrinsic coagulation cascade, involving tissue factor (factor III) and factor Xa (FXa), activates protease-activated receptors (PARs), exacerbating inflammation.
Purpose of the Study:
- To review the interplay between eNOS, coagulation, and PARs in DKD.
- To explore the therapeutic potential of targeting coagulation and PARs in DKD management.
Main Methods:
- Review of existing literature on eNOS, coagulation pathways, and PARs in DKD.
- Analysis of studies involving diabetic mouse models with reduced eNOS expression.
- Examination of the effects of inhibiting coagulation factors or PARs in these models.
Main Results:
- Reduced eNOS expression in diabetic mice correlates with increased renal tissue factor and PAR1/PAR2 expression.
- Pharmaceutical inhibition or genetic deletion of coagulation factors or PARs significantly reduced inflammation in eNOS-deficient diabetic mice.
- These findings highlight a critical pathway linking eNOS dysfunction to coagulation-driven inflammation in DKD.
Conclusions:
- eNOS dysfunction contributes to DKD by promoting a pro-coagulant and inflammatory state.
- Targeting the coagulation cascade and PARs presents a promising therapeutic strategy for DKD.
- Further research into this pathway could lead to novel treatments for patients with diabetic kidney disease.
