Activation of protease‐activated receptor 2 is associated with blood pressure regulation and proteinuria reduction in metabolic syndrome

Abstract

Metabolic syndrome (MetS) increases the risk of kidney disease. In SHRSP.Z‐Leprfa/IzmDmcr (SHRSP.ZF) rats with MetS, protease‐activated receptor 2 (PAR2)‐mediated vasorelaxation is preserved in the aorta at 20 weeks of age (weeks) via enhancement of nitric oxide production but impaired at 30 weeks by oxidative stress. However, impairment of PAR2‐mediated vasorelaxation of renal arteries and its possible implications for kidney disease are unclear. We used organ baths to assess PAR2‐mediated vasorelaxation of isolated renal arteries, colorimetric methods to measure urinary protein levels as an index of renal function, and western blot to determine expression of PAR2 and nephrin proteins in the kidneys of SHRSP.ZF rats at 10, 20, and 30 weeks. We assessed renal arteries and kidney function for effects of orally administered GB88, a pathway‐dependent PAR2 antagonist, from 10 to 18 weeks, and azilsartan, an angiotensin II type 1 receptor blocker, from 13 to 23 weeks. PAR2‐mediated vasorelaxation was slightly lower at 20 weeks and attenuated significantly at 30 weeks compared with those at 10 weeks. Urinary protein levels were increased at 20 and 30 weeks. Decreased protein expression of PAR2 and nephrin in the kidney were observed at 30 weeks. Administration of GB88 increased blood pressure (BP) and proteinuria. Azilsartan reduced the high BP and the impaired PAR2‐mediated vasorelaxation, but did not restore the increase in urinary protein levels and decreased PAR2 and nephrin protein expression in the kidney. PAR2 activation in the kidney may be associated with maintenance of BP and urinary protein excretion in MetS.

Life without Proteinase Activated Receptor 2 (PAR2) Alters Body Composition and Glucose Tolerance in Mice

“…It is quite possible that aging with a complete absence of PAR2 leads to a compensatory adaptation that changes the phenotype observed in young mice. Interestingly, Maruyama et al [ 16 ] demonstrated an age-related increase in body mass with a decline in PAR2 expression in aortas of spontaneous hypertensive rats (SHRSO.ZF), suggesting, albeit not in adipose tissue, that PAR2 expression is not related to weight gain. Further it is important to point out that interventions that prevent high-fat diet induced obesity may, or may not, reduce age-related obesity [ 6 , 17 ], indicating that the slow gradual increase in adiposity with aging is distinct from the rapid weight gain observed with high-fat feeding regimens.…”

Tryptase and Exogenous Trypsin: Mechanisms and Ophthalmic Applications

“…According to existing studies, the small-molecule inhibitor GB88 blocks some PAR2-mediated signalling pathways, but not all of them, and is therefore a useful research tool. 87 , 88 Small molecule PAR2 ligands with differential effects on downstream pathways may also be sought. However, there is a need for multiple small molecule PAR2 ligands with differential effects on downstream pathways, in order to improve clinical efficacy and reduce the frequency of adverse events.…”