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1、Interaction between Renal Medullary PGE2 and (P)RR in Diabetic Nephropathy and Hypertension,Tianxin Yang1,2 and Weidong Wang1 1Institute of Hypertension, Sun Yat-sen University School of Medicine; 2Department of Internal Medicine, University of Utah,Prevalence of CKD,CDC 2010,Incident Rate of ESRD,N
2、IDDK 2010,ESRD Costs,NIDDK 2010,Diabetes,Hypertension,Glomerulonephritis,PKD,Kidney stones,Drugs,RAS,Proteinuria,Podocyte damage,Diabetes Mellitus and Diabetic Nephropathy,Nearly 26 million Americans have diabetes, according to new estimates from the Centers for Disease Control and Prevention (CDC).
3、 In addition, 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 American
4、s of all 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 f
5、or 2011, CDC,Annual Number (in Thousands) of New Cases of Diagnosed Diabetes Among Adults Aged 1879 Years, United States, 19802010 From 1980 through 2010, the number of adults in the United States aged 1879 with newly diagnosed diabetes more than tripled from 493,000 in 1980 to over 1.7 million in 2
6、010. The number of new cases of diabetes has increased since the early 1990s. From 2008 through 2010, the number of new cases of diagnosed diabetes has shown little change.,National Diabetes Fact Sheet for 2011, CDC,Number (in Millions) of Civilian, Noninstitutionalized Adults with Diagnosed Diabete
7、s, United States, 19802010From 1980 through 2010, the number of U.S. adults aged 18 years or older with diagnosed diabetes has more than tripled (from 5.5 million to 20.7 million).,National Diabetes Fact Sheet for 2011, CDC,The overall prevalences of total diabetes (previously diagnosed plus previou
8、sly 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 heart rate, elevated systolic blood pressure, elevated serum triglyceride l
9、evel, 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 2010,EpidemiologyDiabetic nephropathy is the most common cause of chronic kidney failure and end-stage kidney disease in the United
10、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. Furthermore, once nephropathy develops, the greatest rate of progression is seen in p
11、atients 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主要病因，在我们国家主要病因仍为原发性肾小球疾病，但糖尿病肾病的发病率有逐年增高的趋势。,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20年出现，病程呈进展性,大约1/3的糖尿病病人有肾脏受累,糖尿病肾病,Diabetic nephropathy, also
12、known as nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive 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
13、is a prime indication for dialysis in many Western countries.,(Pro)renin Receptor and Diabetic Nephropathy,图1. 肾素-血管紧张素系统与糖尿病肾病的治疗策略,RAS,(Pro)Renin Receptor (PRR)：A New Component of the RAS,Batenburg WW, Jan Danser AH. Eur J Pharmacol. 2008 May 1 18. Review.,Systemic RAS,Schematic presentation of th
14、e main steps in the RAAS cascade and sites of action of the RAAS inhibitors,(Pro)renin Receptor and Hypertension,Collecting Duct Renin System,AngII,膜磷脂,花生四烯酸,Prostanoid Synthesis Pathway,mPGES-1,Ang II Stmulates (P)RR Expression in Primary Rat IMCD Cells,Ang II Stimulates COX-2 Expression in Primary
15、 Rat IMCD Cells,Control,Ang II (4 hr),Ang II (12 hr),Ang II (8 hr),43 kDa,COX-2,P0.05,PRR Protein Expression in IMCD Cells after 12 Hours of Ang II Treatment with or without NS-398,Ang II,P0.05,P0.01,PRR,43 kDa,Ang II + NS-398,Vehicle,Medium Renin Activity,P0.05,P0.05,Effect of Exogenous PGE2 on PRR
16、 Expression,Exogenous PGE2 Reverses the Effect of NS-398,Effects of Structurally Distinct EP4 Antagonists,43 kDa,43 kDa,Summary of Results with 3 EP Antagonists,Ang II,Effect of EP4 Agonist on PRR Expression,CTR,CAY10598,Role of cAMP-PKA Pathway in Control of Baseline PRR Protein Expression in IMCD Cells,CTR,H89,CTR,Forskolin,43 kDa,43 kDa,PRR,PRR,PRR Protein Expression in Rat Renal Medulla after 2- Weeks of Ang II infusion with or without Celecoxib,
