The Role And Mechanism Of TRP Channels On The High Salt-induced Hypertension And Target Organ Damage

Backgroud and objective:The transient receptor potential?TRP?family is a non-selective cation channel.Different TRP channels have different permeability selectivity for cations such as Ca²⁺,Mg²⁺,Na⁺ and H⁺.TRP channel dysfunction is involved in the pathogenesis of some systemic diseases.Transient receptor potential vanilloid 4?TRPV4?is also a member of the TRP family,which is mainly mediated Ca²⁺ influx.Previous study reported that the activation of TRPV4 channel play a role in cardiovascular protection,and it can be activated by apigenin,a specific dietary factor.Transient receptor potential polycystin 2?TRPP2?is a channel encoded by the PKD2L1 gene.Initially,mutation of PKD gene was found to be linked with human autosomal dominant polycystic kidney disease?ADPKD?.Further studies have shown that the TRPP2 channel deficiency is closely related to cardiovascular disease as well.High salt is one of the most important environmental factors which contributes to hypertension.High salt intake is often accompanied by elevated blood pressure.Hypertension can lead to a variety of target organ damage,such as cardiac hypertrophy,kidney injury,atherosclerosis and stroke.Epidemiological investigation demonstrated that disparate dietetic element can lower blood pressure and improve cardiovascular function.The different way of diet can effectively reduce blood pressure and improve cardiovascular function by reducing the intake of sodium,increase potassium intake,and enventrually improve the target organ damage.Apigenin is one of the plant polyphenols,which can reduce blood pressure,vasodilation,antioxidant and other cardiovascular protection effect.Whether dietary apigenin on high salt induced hypertension renal damage possessing a protective effect is unclear.In the crowd study,the increased dietary salt intake is significantly associated with the prevalence of cardiac hypertrophy increasing,which accompanies with the left ventricular weight,left ventricular posterior wall thickness,and ventricular septal thickness augment.Cardiovascular diseases are a serious threaten to human health and life.However,the restriction of salt intake is very difficult and difficult to achieve the desired results.Reducing the risk of high salt on cardiac hypertrophy and lowering salt intake for the prevention and treatment of ardiac hypertrophy are essential to the occurrence and development of cardiac hypertrophy.Materials and methods:The study was conducted in two parts.Part 1: Dietary apigenin was used to treat DOCA-salt hypertensive rats for 4 weeks,and then monitor blood pressure and clarify the antihypertensive effect of activation of TRPV4 on salt-sensitive hypertension.To observe the kidney histological staining of DOCA-salt hypertensive rats,clarify the protective effect of activation TRPV4 on DOCA-salt hypertension and its target organ damage.Manipulate TRPV4 channel to illuminate the mechanism of apigenin renal protection.Part II:,High salt diet interventies TRPP2 KO and WT mice for 24 weeks.Clarify the effect of TRPP2 channel and long-term high salt intake on cardiac structure and function in mice.The effect of high salt on myocardial mitochondrial respiratory function was analyzed by high-resolution respiratory function analyzer.Explore the role of TRPP2 in mitochondrial respiratory function and the pathogenesis of high salt inducing cardiac hypertrophy.1.Vivo studies:?1?Monitor the rat blood pressure by tail-cuff plethysmography and 24 hours ambulatory systolic pressure measurements.?2?Observe the changes of the kidneys by histopathological staining.?3?Collect the 24 hours urine and measure urine albumin content.?4?Evaluate the vascular function of renal interstitial artery by small vessel tension measurement technique.?5?Assess the changes of cardiac structure and function in mice by ultrasonography?6?Experimental animal monitoring system to determine the changes in energy metabolism in mice?7?Measure the the changes of myocardial mitochondrial respiratory function.2.Vitro Study: Detect the expression of AMPK/SITR 1 protein and renal fibrosis related protein in HBZY-1 cells.Observe the expression of NCX1 and NHE1 protein and the mRNA level were in H9C2 cells.Measure the cell and mitochondrial Ca²⁺ uptake in H9C2 cells.Result:?1?Dctication fo TRPV4 reduces DOCA-salt hypertensive rats blood pressure,improves DOCA-salt hypertensive rats renal interstitial artery diastolic function,reduces urinary albumin,and antagonizes renal fibrosis.?2?Dietary apigenin activates TRPV4 channel mediating Ca²⁺ influx.?3?Activation of TRPV4 can induce AMPK phosphorylation and SIRT1 activation by increasing of intracellular Ca²⁺ concentration,which can inhibit TGF?1-Smad2/3 signaling pathway.?4?Long-term high salt intake leads to impaired cardiac function and cardiac hypertrophy in mice.TRPP2 deficiency increased this effect.?5?Long-term high salt intake inhibits mitochondrial respiratory function,and TRPP2 deletion increased mitochondrial respiratory dysfunction.?6?The lack of TRPP2 compensatorily increase protein expression of NCX1,which involves in high salt induced cardiomyocyte Ca²⁺ homeostasis regulation.Conclusion:?1?Activation of TRPV4 by dietary apigenin reduces DOCA-salt hypertensive rats blood pressure,and posessed a protective effect on renal damage by salt-induced hypertension.?2?Activation of TRPV4 contributes to Ca²⁺ influx,and the increase of intracellular Ca²⁺ concentration induces AMPK phosphorylation and SIRT1 activation,which can suppress the TGF-?1/Smad2/3 pathway.Thereby,activation of TRPV4 inhibits renal fibrosis and play a protective role in the kidney damage.?3?TRPP2 deletion increases the expression of NCX1,which will aggravate the high salt-induced myocardial mitochondrial Ca²⁺ overload,lead to myocardial mitochondrial respiratory dysfunction and involve in cardiac hypertrophy.