Coagulation, Protease-Activated Receptors, And Diabetic Kidney Disease: Lessons From ENOS-Deficient Mice
Feb 02, 2024
Dual Blockade of PAR1 and PAR2 in Diabetic Mice with Reduced eNOS
We have demonstrated that PAR1 and PAR2 cooperatively contribute to DKD pathogenesis (Mitsui et al. 2020). In this study, male type I diabetic Akita mice heterozygous for eNOS (Ins2Akita/+; eNOS+/-) were used as a model of DKD. These mice were treated with vehicle, PAR1 antagonist (E5555, 60 mg/kg/day), PAR2 antagonist (FSLLRY, 3 mg/kg/day), or E5555 + FSLLRY for 4 weeks. Administration of the PAR1 or PAR2 antagonist alone attenuated glomerular injury, such as mesangial expansion and collagen IV deposition, compared to administration of a vehicle. Synergistic therapeutic effects of both PAR1 and PAR2 inhibition were observed, and the urinary albumin-to-creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 +
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FSLLRY compared with the vehicle administration. Furthermore, dual blockade of PAR1 and PAR2 by E5555 + FSLLRY synergistically ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and deposition of type IV collagen. The expression levels of inflammation- and fibrosis-related genes in the kidneys were also reduced (Table 1).
We focused on the pro-inflammatory effects of PAR1 and PAR2 agonists on human endothelial cells (Mitsui et al. 2020). The results showed that stimulation with both PAR1 and PAR2 agonists synergistically increased the expression levels of MCP1 and PAI1 mRNA. The effect of the PAR1 agonist was blocked by an NF-κB inhibitor, whereas that of the PAR2 agonist was blocked by NF-kB and MAPK inhibitors. Collectively, PAR1 and PAR2 cooperatively contribute to vascular inflammation and DKD through different signaling pathways (Fig. 3).
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Conclusion
In this review, we focused on the relationship between the coagulation protease-PAR pathway and eNOS deficiency in diabetic mice. Low production of eNOS is linked to hypercoagulability and increased PAR signaling, which are harmful in DKD. These findings may indicate their pathological roles in the advanced or later phase of DKD (e.g., with renal failure and/or massive proteinuria). Oral FXa inhibitors are widely used to prevent thrombosis (Patel et al. 2011; Robertson et al. 2015). Their use in the treatment of DKD is a promising option. Furthermore, some PAR1 antagonists, including atopaxar and vorapaxar, can be used in antiplatelet therapy to prevent acute coronary syndrome (Goto et al. 2010; Tricoci et al. 2012). In addition, there is remarkable progress in the development of PAR2 antagonists (Lim et al. 2013; Cheng et al. 2017; Jiang et al. 2018), and they can be novel therapeutic options to treat patients with DKD.
Acknowledgments
This study was supported by the Gonryo Medical Foundation. We would like to thank Editage (https://www. editage.com) for English language editing. Conflict of Interest The authors declare no conflict of interest.
References
Afkarian, M., Sachs, M.C., Kestenbaum, B., Hirsch, I.B., Tuttle, K.R., Himmelfarb, J. & de Boer, I.H. (2013)
Kidney disease and increased mortality risk in type 2 diabetes. J. Am. Soc. Nephrol., 24, 302-308. Azushima, K., Gurley, S.B. & Coffman, T.M. (2018)
Modeling diabetic nephropathy in mice. Nat. Rev. Nephrol., 14, 48-56. Brosius, F.C., Alpers, C.E., Bottinger, E.P., Breyer, M.D., Coffman, T.M., Gurley, S.B., Harris, R.C., Kakoki, M., Kretzler, M., Leiter, E.H., Levi, M., McIndoe, R.A., Sharma, K., Smithies, O., Susztak, K., et al. (2009) Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol., 20, 2503-2512.
Camerer, E., Huang, W. & Coughlin, S.R. (2000) Tissue factorand factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc. Natl. Acad. Sci. U. S. A., 97, 5255-5260. Chen, D. & Dorling, A. (2009)
Critical roles for thrombin in acute and chronic inflammation. J. Thromb. Haemost., 7 Suppl 1, 122-126. Cheng, H., Wang, H., Fan, X., Paueksakon, P. & Harris, R.C. (2012) Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/ db mice. Kidney Int.,
82, 1176-1183. Cheng, R.K.Y., Fiez-Vandal, C., Schlenker, O., Edman, K., Aggeler, B., Brown, D.G., Brown, G.A., Cooke, R.M., Dumelin, C.E., Doré, A.S., Geschwindner, S., Grebner, C., Hermansson, N.O., Jazayeri, A., Johansson, P., et al. (2017) Structural insight into allosteric modulation of protease-activated receptor 2. Nature, 545, 112-115.
