Obesity mediated hypertension and renal dysfunction Gergely Bodor Marion Hervouet Nicky Honnef Mariarosaria Malgadi Julie Robert Tutor: Pr Alina Parvu
Objectives 1. Introduction 2. Renal structural and functional changes in obesity 3. Role of adipocytes mediators in obesity 4. Renin angiotensin aldosterone system in obesity 5. Sympathetic nervous system in obesity 6. Obesity paradox 7. Conclusion
1.Introduction
Overweight and obesity «abnormal or excessive fat accumulation that may impair health» WHO BMI = weight / height² Limits of BMI: OBESITY = HETEROGENOUS CONDITION Others markers of obesity: waist circumference MRI,, cumputed tomography imaging, impedence Tchernof A, Després JP 2014
Abdominal obesity waist circumference > 102 cm (men) > 88 cm (women) Expansion of dysfunctional subcutaneous adipose tissue Ectopic triglyceride storage = Risk factors Tchernof A, Després JP 2014
Visceral obesity Excess intra-abdominal adipose tissue accumulation = main driving force for most of the disorders associated with obesity Tchernof A, Després JP 2014
CKD = Chronic Kidney Disease «The presence of reduced kidney function, or kidney damage, for a period of 3 months or greater» - Chronicity - Constant progression - Systemic consequences Table 2: Stage Description egfr(ml/min/1.73 m2) 1 CKD with normal or increased GFR >90 2 Mild GFR loss 60 89 3 Moderate GFR loss 30 59 4 Severe GFR loss 15 29 5 Kidney failure <15 or dialysis Garland, J. S. (2014).
MS: metabolic syndrome; HBP: high blood pressure; DM: diabetes mellitus; CVD: cardiovascular disease; CKD: chronic kidney disease.
Mechanisms of CKD in obesity Indirect Hypertension Direct Hemodynamic effects Hormonal effects Diabetes Na reabsorption Fatty kidney Compression Compensatory mechanism Increased filtration Vasodilatation Proteinuria ESRD CKD Glomerulosclerosis
The role of adipocytes mediators in obesity
Cells, and adipokines of WAT Preadipocytes Adipocytes Fibroblasts Macrophages Leukocytes Endothel cells Leptin Adiponectin Visfatin Resistin
Resistin Antagonizes insulin Increases Endothelin-1 production Effects of ET-1: Vasoconstrictor tone Nitric oxide bioavailability In CKD Endothelial dysfunction GFR Briffa JF; 2013
Visfatin TNF-α, IL-6, IL-1B ROS Renin and Angiotensinogen mrna Inflammation Oxydative stress renal pathology GFR Sommer G; 2008
Adiponectin Effects: Cardioprotective: Insulin sensitivity ROS production Acivates AMP activated protein kinase In podocytes: downregulation of NADPH oxidase Adiponectin levels are correlated: Negatively: Body fat %, Type-2 diabetes, Insulin resistance, Hypertension Positively: Albuminuria, CKD, Type-2 diabetes Sweiss N; 2014
Leptin SNS activation Hall JE; 2005
Hall JE; 2005 Leptin-receptor metiated pathways
Leptin in the kidneys ROS, ET-1 HT,Endothelial dysfunction glomerulosclerosis TGF-β1 EC matrix expansion Alix PM; 2014
nflamation of WAT in obesity Overstretched adipocytes TNF-α, IL-6, MCP-1 Systemic subclinical inflammatory response
OBESITY INFLAMMATION OXIDATIVE STRESS CKD
Renin angiotensin aldosterone system in obesity
Blood pressure Juxtaglomerular cells PHYSIOLOGICALLY Angiotensinogen Cardio-pulmonar baroreceptor (SNS) Macula densa renin ACE Angiotensin I Angiotensin II Aldosterone Arteriolar Vasoconstriction Vascular tone ENaC and Na/K pump Na reabsorption Fluid volume Blood pressure
Adipose tissue VISCERAL OBESITY Production of bioactives molecules RAAS receptors and components RAAS activation SNS angiotensinogen Adipose tissue differenciation and proliferation Aldosterone Activation of mineralocorticoides and glucocorticoides receptors Blood Pressure 1 Garland (2014) 2 Kurukulasurya (2011)
Obesity CKD Hypertension
OBESITY PARADOX????!
Therapeutic perspectives
Obesity First line therapy Body weight reduction obesity - Calorie intake - Physical exercise Not effective in producing long term weight loss Second line therapy pharmacological treatment bariatric surgery (Bidani, 2013; Lambers Heerspink, 2012; XU, 2014)
Pharmacological treatments Retrieved from: http://www.google.fr/imgres?imgurl=http%3a%2f%2fupload.wikimedia.org
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