1. Slide Source Hypertension Online www.hypertensiononline.org Copyright Notice You are authorized to use these slides subject to the following terms, conditions and exceptions: They are to be used solely for personal, noncommercial, informational, and educational purposes. They may not to be modified in any way. Copyright information or other proprietary notices may not be removed, changed, or altered. The authors, contributors, and editorial staff have made every effort to contact holders of copyright to obtain permission to reproduce copyright material. However, if any permissions have been inadvertently overlooked, Baylor College of Medicine will be pleased to make the necessary and reasonable arrangements. To request permission to reproduce or modify a slide or image from Hypertension Online, please contact us at ccit@bcm.tmc.edu.

2. Slide Source Hypertension Online www.hypertensiononline.org Hypertension and Renal Disease: Mechanisms Scanning electron (top) and light (bottom) micrographs of a human glomerulus trc.ucdavis.edu/mjguinan/apc100/modules/ Urinary/mammal/cortex1/cortex.html trc.ucdavis.edu/mjguinan/apc100/modules/ Urinary/mammal/glomeruli0/glomeruli.html

3. Slide Source Hypertension Online www.hypertensiononline.org Glomerulus Mesangial Matrix Efferent Renal Arteriole Mesangial Cells Renal Sympathetic Nerves Bowman’s Capsule Distal Convoluted Tubule Proximal Convoluted Tubule Adventitial Mast Cell/Macrophage Components of the Normal Nephron Vascular Smooth Muscle Cells Juxtaglomerular Cells Macula Densa

4. Slide Source Hypertension Online www.hypertensiononline.org Glomerular hypertension Hyperfiltration Glomerular barrier dysfunction Proteinuria Mesangial cell hyperplasia Intrarenal inflammatory processes Endothelial dysfunction VSMC proliferation Normal Kidney Mechanisms of Renal Damage in HTN Mechanisms B l o o d P r e s s u r e

5. Slide Source Hypertension Online www.hypertensiononline.org Functional Decrease in GFR Proteinuria Structural Glomular basement membrane changes Expanded mesangial matrix Glomerulosclerosis Tubulo-interstitial fibrosis B l o o d P r e s s u r e Consequences of Renal Damage in HTN Consequences Renal Failure

6. Slide Source Hypertension Online www.hypertensiononline.org Effects of Vasodilators in the Normal Kidney L-Arginine NO eNOS (-) L-Citrulline EDHF(s) Pgl 2 (-) PMN MM Platelet (-) VSMC EC

7. Slide Source Hypertension Online www.hypertensiononline.org Imbalance in Factors Affecting Vascular Tone and Structure Nephron destruction and renal failure Angiotensin II Catecholamines Endothelin-1 ROS Cytokines EDCF Nitric Oxide Prostacyclin Bradykinin EDHF Constrictors/ Growth Promoters Dilators/ Growth Inhibitors Vascular tone and structure EDHF= endothelium-derived hyperpolarizing factors ROS= reactive oxygen species EDCF= endothelium-derived constricting factors

8. Slide Source Hypertension Online www.hypertensiononline.org + =OONO _ (-) ROS Reduces the Biological Effects of NO O2O2 Afferent Arteriole L-Arginine NO eNOS L-Citrulline NE VSMC PMN MM Fibroblast EC Mast cell (+)

9. Slide Source Hypertension Online www.hypertensiononline.org Renin-Angiotensin Cascade Angiotensinogen  Angiotensin I  Angiotensin II AT 1 AT 2 AT n Bradykinin Inactive peptides Non-renin (eg tPA) Non-ACE (eg chymase) ACE Renin

10. Slide Source Hypertension Online www.hypertensiononline.org Angiotensin II (Ang II) generated in the afferent arteriole interacts with AT 1 receptors on cellular components of the nephron Angiotensinogen Ang I Renin ACE Ang II AT 1 R = AT 1 Receptor

11. Slide Source Hypertension Online www.hypertensiononline.org Role of Angiotensin II in Chronic Renal Disease  Adhesion molecules  Chemotactic factors  Cell growth  Apoptosis  TGF-, CTGF  PAI-1  Glomerular capillary pressure  Single nephron GFR Macrophage infiltration Angiotensin II Mechanical stress Mesangial changes Oxidative stress Proteinuria NF-B activation Glomerulosclerosis & Tubulo-interstitial fibrosis Renal disease Nephron loss Adapted from Berk B. 2001.

12. Slide Source Hypertension Online www.hypertensiononline.org Angiotensin II Induces Oxidative Stress in the Kidney Stimulation of Membrane NOX-1 Oxidase* –Increased superoxide (O 2 ) –Increased thiobarbituric acid reactive substances –Increased oxidized lipids –Increased tissue protein carbonyl content Induction of Heme Oxidase-1 (HO-1) Activation of NF-B –Increased inflammatory cytokines *NAD(P)H Oxidase

13. Slide Source Hypertension Online www.hypertensiononline.org O 2 H 2 O 2 H 2 O+O 2 O2O2 Renal Sources of ROS NOX-1 oxidase* Xanthine oxidase Heme oxygenase–1 Cyclo-oxygenase Lipoxygenase Cytochrome P 450 mono-oxygenase Mitochondrial oxidative phosphorylation *NADP(H) oxidase Superoxide dismutase Catalase

14. Slide Source Hypertension Online www.hypertensiononline.org  O 2 Endothelial Cells and  H 2 O 2 Vascular Smooth Muscle Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors Endothelial Dysfunction Apoptosis Vasoconstriction Leukocyte adhesion Lipid deposition Thrombosis VSMC growth Hypertension Smoking Diabetes LDL HomocysteineEstrogen deficiency

15. Slide Source Hypertension Online www.hypertensiononline.org Pivotal Role of ROS in Stimulus-Induced EC and VSMC Growth, Survival, and Apoptosis PDGF, Thrombin, Norepinephrine, Ang II, TNF, Ox-LDL, High Glucose, VEGF ROS Arachidonate Metabolism Mitochondrial Electron Transport Chain Cytochrome P 450 NOX-1 Oxidase Xanthine Oxidase Growth or Hypertrophy Survival Apoptosis   Caspases  NF-B  Akt  ERKs  JNKs SAPKs  p 38 MAPK Potential Targets of ROS Sources of ROS Growth/Death Survival Signals

16. Slide Source Hypertension Online www.hypertensiononline.org Pathologic Processes Leading to Glomerular Injury and Proteinuria Ang II Increased glomerular pressure Ang II Urinary protein Glucose AGEs Glycoxidation (glycation) Efferent arteriolar constriction =angiotensin AT 1 receptor

17. Slide Source Hypertension Online www.hypertensiononline.org Vascular and/or Tubular Injury Glomerular cells Tubular cells Lymphocytes Macrophages Fibroblasts TGF- ET-1 CTGF Ang II PAI-1 PDGF bFGF TNF- IL-1 FIBROSIS Fibrosis and Nephron Loss: A Renal Response to Injury

18. Slide Source Hypertension Online www.hypertensiononline.org TGF- TGF- plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units

19. Slide Source Hypertension Online www.hypertensiononline.org bFGF PDGF Ang II TSP1 TGF- O2O2 TGF- plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units O2O2

20. Slide Source Hypertension Online www.hypertensiononline.org TIMP bFGF PDGF Ang II Proteases (-) (+) TSP1 ET-1 PAI-1 O2O2 TGF- TGF- plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units O2O2

21. Slide Source Hypertension Online www.hypertensiononline.org Angiotensin II: Role in Renal Injury Angiotensin II AT 1 R AT 2 R NF-B TNFR1 TNFR2 Angiotensinogen Fibroblasts Proliferation and differentiation Matrix FIBROSIS Inflammation Cellular adhesion molecules Tubule cells TNF- ++ Profibrotic cytokines

22. Slide Source Hypertension Online www.hypertensiononline.org Aldosterone Promotes Renal Fibrosis by Multiple Mechanisms AdrenalVascular Aldosterone PAI-1 Nitric oxide synthesis Na + influx into VSMC Norepinephrine uptake into VSMC Angiotensin II AT1R binding of Ang II StimulatesInhibits Fibroblast collagen synthesis

23. Slide Source Hypertension Online www.hypertensiononline.org Pathways Leading To Progressive Renal Failure Renal growth factor & cytokine activation Fibrogenesis Systemic hypertension Progressive Loss of Filtration Surface Area GFR Renal injury Nephron mass Glomerular hypertension Renal scarring Hyperlipidemia Filtration of plasma proteins (Proteinuria)  Proximal tubule protein uptake Renal microvascular injury Influx of monocytes and macrophages Transdifferentiation of renal cells to fibroblast phenotype Brenner BM, Keane WF. 2001.