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Protease-activated receptors in diabetic complications

Diabetic nephropathy is a leading cause of renal failure and is a major life-threatening problem. Although pharmacological inhibition of the renin-angiotensin system slows progression of diabetic nephropathy, patient prognosis remains poor. We have clarified that lack or reduced expression of endothelial nitric oxide synthase (eNOS, Nos3) exacerbates diabetic nephropathy, which is associated with increased expression and activity of renal tissue factor (TF), an initiator of the coagulation cascade. Anti-TF neutralizing antibody reduced inflammation in diabetic nephropathy. Coagulation proteases contribute to tissue injury mediated by protease-activated receptors (PARs). PAR2 is activated by TF- coagulation factor VIIa (FVIIa) complex and coagulation factor Xa (FXa) and up-regulates inflammation and fibrosis. Most recently we reported that lack of PAR2 are protective against diabetic nephropathy. Interestingly, these mice have reduced PAR1 expression in the kidney. Both PAR1 and PAR2 are proinflammatory, and PAR1 is known to be increased in diabetic kidneys. Accordingly, PAR2 and possibly PAR1 are promising target for diabetic complications. Specific Aim 1 will clarify whether inhibiting both PAR1 and PAR2 is more effective in preventing diabetic nephropathy than inhibiting PAR2 alone. We generate male mice lacking PAR2 (F2rl1-/-) or having wild type PAR2 (F2rl1+/+) on Nos3+/- and Ins2Akita/+ background. These mice will be divided into two groups and treated or not treated with PAR1 specific antagonist E5555. Specific Aim 2 will identify chemical compounds with PAR2 inhibiting properties. PAR2 antagonists will be screened using several chemical compound libraries. We add library compounds and calcium sensitive dye Fluo4 to human endothelial cell line EA.hy926, and look for compounds that inhibit the increase in intracellular calcium by a PAR2 agonist peptide 2f-LIGRLO. Selectivity of the compounds for PAR2 and PAR1 will be evaluated by inhibition of the increase in intracellular calcium by a PAR1 agonist.

Progress Reports


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Application	Complete Date	Report	Options
Protease-activated receptors in diabetic complications (Takahashi, Nobuyuki)	11/17/2017	View Progress Report Document

Annual Reports

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Publication	Submitted By	PubMed ID	Status
Year: 2020; Items: 1
Dual blockade of protease-activated receptor 1 and 2 additively ameliorates diabetic kidney disease. Mitsui S, Oe Y, Sekimoto A, Sato E, Hashizume Y, Yamakage S, Kumakura S, Sato H, Ito S, Takahashi N American journal of physiology. Renal physiology, 2020 (318), F1067 - F1073	Takahashi, Nobuyuki	32200667	Published
Year: 2012; Items: 1
eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype. Li F, Hagaman JR, Kim HS, Maeda N, Jennette JC, Faber JE, Karumanchi SA, Smithies O, Takahashi N Journal of the American Society of Nephrology : JASN, 2012 (23), 652 - 660	Takahashi, Nobuyuki	22282588	Published
Year: 2011; Items: 2
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Wang CH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, Takahashi N Proceedings of the National Academy of Sciences of the United States of America, 2011 (108), 2070 - 5	Takahashi, Nobuyuki	21245338	Published
A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Wang CH, Li F, Hiller S, Kim HS, Maeda N, Smithies O, Takahashi N Proceedings of the National Academy of Sciences of the United States of America, 2011 (108), 2070 - 2075	Smithies, Oliver	21245338	Published
Year: 2010; Items: 2
Loss of bradykinin signaling does not accelerate the development of cardiac dysfunction in type 1 diabetic akita mice. Wende AR, Soto J, Olsen CD, Pires KM, Schell JC, Larrieu-Lahargue F, Litwin SE, Kakoki M, Takahashi N, Smithies O, Abel ED Endocrinology, 2010 (151), 3536 - 3542	Smithies, Oliver	20501666	Published
The renin angiotensin system and the metabolic syndrome. Wang CH, Li F, Takahashi N The open hypertension journal, 2010 (3), 1 - 13	Takahashi, Nobuyuki	21132096	Published

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Title	Type	Version	Investigator(s)
Breeding Scheme and Selection of Animals for DCC Experiments	Breeding	1	Maeda, Nobuyo Smithies, Oliver Takahashi, Nobuyuki

Name

Description

Steering Committee

The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the External Evaluation Committee

Nephropathy

The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.

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