肾髓质PGE2及肾素受体在糖尿病肾病和高血压中的作用ppt课件

1、Interaction 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 UtahPrevalence of CKD CDC 2021Incident Rate of ESRDNIDDK

2、 2021ESRD CostsNIDDK 2021DiabetesHypertensionGlomerulonephritisPKDKidney stonesDrugsRASProteinuria Podocyte damage Diabetes Mellitus and Diabetic NephropathyNearly 26 million Americans have diabetes, according to new estimates from the Centers for Disease Control and Prevention (CDC). In addition, a

3、n 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 ages,

4、and 11.3 percent of adults aged 20 and older, according to the National Diabetes Fact Sheet for 2021. 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 2021, CDCThe

5、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, increased hear

6、t 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 2021Epidemiology Diabetic nephropathy is the most common cause

7、 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 2021. People with both type 1 and type 2 diabetes are at risk. The risk is higher if blood-glucose levels are poorly controlled. Furthermore, on

8、ce 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.糖尿病肾病在西方国家是导致慢性肾病和终末期肾病的最糖尿病肾病在西方国家是导致慢性肾病和终末期肾病的最主要病因，在我们国家主要病因仍为原发性肾小球疾病，主要病因，在我们国家主要病因仍为原

9、发性肾小球疾病，但糖尿病肾病的发病率有逐年增高的趋势。但糖尿病肾病的发病率有逐年增高的趋势。以肾小球病变为特征的糖尿病肾病大约在糖尿病诊断之后以肾小球病变为特征的糖尿病肾病大约在糖尿病诊断之后15至至20年出现，病程呈进展性年出现，病程呈进展性大约大约1/3的糖尿病病人有肾脏受累的糖尿病病人有肾脏受累 糖尿病肾病糖尿病肾病Diabetic nephropathy, also known as nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney dis

10、ease 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.(Pro)renin Receptor and Diabetic Nephropathy图图1. 肾

11、素肾素-血管紧张素系统与糖尿病肾病的治疗战略血管紧张素系统与糖尿病肾病的治疗战略RAS (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. 2021 May 1 18. Review.Systemic RASSystemic RASSchematic presentation of the main steps in the RAAS cascad

12、e and sites of action of the RAAS inhibitors (Pro)renin Receptor and HypertensionCollecting Duct Renin SystemCollecting Duct Renin SystemAngII膜磷脂膜磷脂花生四烯酸花生四烯酸Prostanoid Synthesis PathwaymPGES-1Ang II Stmulates (P)RR Expression in Ang II Stmulates (P)RR Expression in Primary Rat IMCD CellsPrimary Rat

13、 IMCD CellsControlAngIIPRR43 kDa-Actin43 kDaP0.05Ang II Stimulates COX-2 Expression in Primary Rat IMCD CellsControlAng II (4 hr)Ang II (12 hr)Ang II (8 hr)43 kDaCOX-2P0.05PRR Protein Expression in IMCD Cells after 12 Hours of Ang II Treatment with or without NS-398 Ang II P0.05P0.01 PRR43 kDaAng II

14、 + NS-398 VehicleMedium Renin ActivityP0.05P0.05Effect of Exogenous PGE2 on PRR Expression PRRVehiclePGE2P0.0143 kDaExogenous PGE2 Reverses the Effect of NS-398Ang II 43 kDaP0.05Ang II + NS398 Ang II + NS398 + PGE2 PRREffects of Structurally Distinct EP4 AntagonistsCTRCTRAng IIAng IIAng II + ONO-AE3

15、-208Ang II + L-16198243 kDa43 kDaSummary of Results with 3 Summary of Results with 3 EP AntagonistsEP AntagonistsP0.01P0.05P0.05VehicleControlEP1 AEP3 AEP4 AAng IIEffect of EP4 Agonist on PRR ExpressionCTRCAY10598Role of cAMP-PKA Pathway in Control of Baseline PRR Protein Expression in IMCD CellsCTR

16、H89CTRForskolin43 kDa43 kDaPRRPRRPRR Protein Expression in Rat Renal Medulla after 2-Weeks of Ang II infusion with or without CelecoxibAng II + Coxib PRRControlAng II43 kDa -ActinP0.05P0.05P0.05P0.05P0.05P0.05BACDHFGECirculatory, Renal Regional, and Urinary Renin Activity and Total Renin Content P0.05P0.05Systolic Blood Pressure Celecoxib Attenuates Albuminuria in AngII-Infused MiceAlbumin excre