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

Limits of BMI: OBESITY = HETEROGENOUS CONDITION

Others markers of obesity:

waist circumference

MRI ,, cumputed tomography imaging, impedence

Overweight and obesity

« abnormal or excessive fat accumulation that may impair health » WHO

BMI = weight / height²

Tchernof A, Després JP 2014

Abdominal obesity

• Expansion of dysfunctional subcutaneous adipose tissue

• Ectopic triglyceride storage

= Risk factors

waist circumference > 102 cm (men)

> 88 cm (women)

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

Diabetes

Direct Hormonal effects

Hemodynamic effects

Fatty kidney

Compression

Na reabsorption

Compensatory mechanism

Increased filtration

Proteinuria

Glomerulosclerosis CKD ESRD

Vasodilatation

The role of adipocytes mediators in obesity

Cells, and adipokines of WAT

Preadipocytes Adipocytes Fibroblasts Macrophages Leukocytes Endothel cells

• Resistin • Leptin • Adiponectin • Visfatin

Resistin

• Antagonizes insulin

• Increases Endothelin-1 production

Effects of ET-1: • Vasoconstrictor tone

• Nitric oxide bioavailability

In CKD Endothelial dysfunction GFR

Briffa JF; 2013

TNF-α, IL-6, IL-1B ROS

Renin and Angiotensinogen mRNA

Inflammation Oxydative stress

renal pathology

GFR

Visfatin

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

Leptin-receptor metiated pathways

Hall JE; 2005

Leptin in the kidneys

ROS, ET-1

TGF-β1 EC matrix expansion

HT,Endothelial dysfunction

glomerulosclerosis

Alix PM; 2014

Inflamation of WAT in obesity

Overstretched adipocytes

TNF-α, IL-6, MCP-1

Systemic subclinical inflammatory response

OBESITY

CKD

INFLAMMATION OXIDATIVE

STRESS

Renin angiotensin aldosterone system in

obesity

Angiotensinogen

Aldosterone

Angiotensin I

Angiotensin II

renin

Blood pressure

ENaC and Na/K pump

Arteriolar Vasoconstriction Vascular tone

Na reabsorption

Fluid volume

ACE

Juxtaglomerular cells

Macula densa

Cardio-pulmonar baroreceptor (SNS)

Blood pressure

PHYSIOLOGICALLY

Adipose tissue Production of bioactives molecules

RAAS receptors and components

angiotensinogen Adipose tissue differenciation and proliferation

Blood Pressure

VISCERAL OBESITY

SNS

Aldosterone

Activation of mineralocorticoides and glucocorticoides receptors

RAAS activation

1 Garland (2014) 2 Kurukulasurya (2011)

Obesity

Hypertension

CKD

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

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Thank you for your attention