腎髓質(zhì)PGE2及腎素受體在糖尿病腎病和高血壓中的作用ppt課件

1、1Interaction between Renal Medullary PGE2 and (P)RR in Diabetic Nephropathy and Hypertension Tianxin Yang1,2 and Weidong Wang11Institute of Hypertension, Sun Yat-sen University School of Medicine; 2Department of Internal Medicine, University of Utah2Prevalence of CKD CDC 20103Incident Rate of ESRDNI

2、DDK 20104ESRD CostsNIDDK 20105DiabetesHypertensionGlomerulonephritisPKDKidney stonesDrugsRASProteinuria Podocyte damage 6Diabetes Mellitus and Diabetic Nephropathy7Nearly 26 million Americans have diabetes, according to new estimates from the Centers for Disease Control and Prevention (CDC). In addi

3、tion, an estimated 79 million U.S. adults have prediabetes, a condition in which blood sugar levels are higher than normal, but not high enough to be diagnosed as diabetes. Prediabetes raises a persons risk of type 2 diabetes, heart disease and stroke.Diabetes affects 8.3 percent of Americans of all

4、 ages, and 11.3 percent of adults aged 20 and older, according to the National Diabetes Fact Sheet for 2011. About 27 percent of those with diabetes7 million Americansdo not know they have the disease. Prediabetes affects 35 percent of adults aged 20 and older.National Diabetes Fact Sheet for 2011,

5、CDC8910The overall prevalences of total diabetes (previously diagnosed plus previously undiagnosed diabetes) and prediabetes were 9.7% and 15.5%, respectively.In the multivariable, multinomial, logit models, male sex, older age, a family history of diabetes, overweight, obesity, central obesity, inc

6、reased heart rate, elevated systolic blood pressure, elevated serum triglyceride level, educational level below college, and urban residence were all significantly associated with an increased risk of diabetes and prediabetes.Yang et al N Eng J Med 201011Epidemiology Diabetic nephropathy is the most

7、 common cause of chronic kidney failure and end-stage kidney disease in the United States, accounting for 44% of all new cases of kidney failure in the United States in 2008. People with both type 1 and type 2 diabetes are at risk. The risk is higher if blood-glucose levels are poorly controlled. Fu

8、rthermore, once nephropathy develops, the greatest rate of progression is seen in patients with poor control of their blood pressure. Also people with high cholesterol level in their blood have much more risk than others.12糖尿病腎病在西方國家是導(dǎo)致慢性腎病和終末期腎病的最主要病因，在我們國家主要病糖尿病腎病在西方國家是導(dǎo)致慢性腎病和終末期腎病的最主要病因，在我們國家主要病因

9、仍為原發(fā)性腎小球疾病，但糖尿病腎病的發(fā)病率有逐年增高的趨勢(shì)。因仍為原發(fā)性腎小球疾病，但糖尿病腎病的發(fā)病率有逐年增高的趨勢(shì)。以腎小球病變?yōu)樘卣鞯奶悄虿∧I病大約在糖尿病診斷之后以腎小球病變?yōu)樘卣鞯奶悄虿∧I病大約在糖尿病診斷之后15至至20年出現(xiàn)，病程呈進(jìn)展性年出現(xiàn)，病程呈進(jìn)展性大約大約1/3的糖尿病病人有腎臟受累的糖尿病病人有腎臟受累 糖尿病腎病糖尿病腎病13Diabetic nephropathy, also known as nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progr

10、essive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime indication for dialysis in many Western countries.14(Pro)renin Receptor and Diabeti

11、c Nephropathy15圖圖1. 腎素腎素-血管緊張素系統(tǒng)與糖尿病腎病的治療策略血管緊張素系統(tǒng)與糖尿病腎病的治療策略16RAS 17(Pro)Renin Receptor (PRR)(Pro)Renin Receptor (PRR)：A New Component of the RAS A New Component of the RAS Batenburg WW, Jan Danser AH. Eur J Pharmacol. 2008 May 1 18. Review.18Systemic RASSystemic RAS19Schematic presentation of the

12、main steps in the RAAS cascade and sites of action of the RAAS inhibitors 20(Pro)renin Receptor and Hypertension21Collecting Duct Renin SystemCollecting Duct Renin SystemAngII2223膜磷脂膜磷脂花生四烯酸花生四烯酸Prostanoid Synthesis PathwaymPGES-124Ang II Stmulates (P)RR Expression in Primary Rat IMCD CellsAng II St

13、mulates (P)RR Expression in Primary Rat IMCD CellsControlAngIIPRR43 kDa-Actin43 kDaP0.0525Ang II Stimulates COX-2 Expression in Primary Rat IMCD CellsControlAng II (4 hr)Ang II (12 hr)Ang II (8 hr)43 kDaCOX-2P0.0526PRR Protein Expression in IMCD Cells after 12 Hours of Ang II Treatment with or witho

14、ut NS-398 Ang II P0.05P0.01 PRR43 kDaAng II + NS-398 Vehicle27Medium Renin ActivityP0.05P0.0528Effect of Exogenous PGE2 on PRR Expression PRRVehiclePGE2P0.0143 kDa29Exogenous PGE2 Reverses the Effect of NS-398Ang II 43 kDaP0.05Ang II + NS398 Ang II + NS398 + PGE2 PRR30Effects of Structurally Distinc

15、t EP4 AntagonistsCTRCTRAng IIAng IIAng II + ONO-AE3-208Ang II + L-16198243 kDa43 kDa31Summary of Results with 3 EP AntagonistsSummary of Results with 3 EP AntagonistsP0.01P0.05P0.05VehicleControlEP1 AEP3 AEP4 AAng II32Effect of EP4 Agonist on PRR ExpressionCTRCAY1059833Role of cAMP-PKA Pathway in Co

16、ntrol of Baseline PRR Protein Expression in IMCD CellsCTRH89CTRForskolin43 kDa43 kDaPRRPRR34PRR Protein Expression in Rat Renal Medulla after 2-Weeks of Ang II infusion with or without CelecoxibAng II + Coxib PRRControlAng II43 kDa -Actin35P0.05P0.05P0.05P0.05P0.05P0.05BACDHFGECirculatory, Renal Regional, and Urinary Renin Activity and Total Renin Content 36P0.05P0.05Systolic Blood Pressure 37Celecoxib Attenuates Albuminuria in AngII-Infused MiceAlbumin excreti