Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Slideshow

  • Be the first to comment

Slideshow

  1. 1. Hypertension and Renal Disease: Mechanisms trc.ucdavis.edu/mjguinan/apc100/modules/ Urinary/mammal/cortex1/cortex.html trc.ucdavis.edu/mjguinan/apc100/modules/ Urinary/mammal/glomeruli0/glomeruli.html Scanning electron (top) and light (bottom) micrographs of a human glomerulus
  2. 2. Components of the Normal Nephron Glomerulus Mesangial Matrix Efferent Renal Arteriole Mesangial Cells Renal Sympathetic Nerves Bowman’s Capsule Distal Convoluted Tubule Proximal Convoluted Tubule Adventitial Mast Cell/Macrophage Vascular Smooth Muscle Cells Juxtaglomerular Cells Macula Densa
  3. 3. Mechanisms of Renal Damage in HTN <ul><li>Glomerular hypertension </li></ul><ul><ul><li>Hyperfiltration </li></ul></ul><ul><li>Glomerular barrier dysfunction </li></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><li>Mesangial cell hyperplasia </li></ul><ul><li>Intrarenal inflammatory processes </li></ul><ul><li>Endothelial dysfunction </li></ul><ul><li>VSMC proliferation </li></ul>Normal Kidney Mechanisms B l o o d P r e s s u r e
  4. 4. Consequences of Renal Damage in HTN <ul><li>Functional </li></ul><ul><ul><li>Decrease in GFR </li></ul></ul><ul><ul><li>Proteinuria </li></ul></ul><ul><li>Structural </li></ul><ul><ul><li>Glomular basement membrane changes </li></ul></ul><ul><ul><li>Expanded mesangial matrix </li></ul></ul><ul><ul><li>Glomerulosclerosis </li></ul></ul><ul><ul><li>Tubulo-interstitial fibrosis </li></ul></ul>B l o o d P r e s s u r e Consequences Renal Failure
  5. 5. Effects of Vasodilators in the Normal Kidney L-Arginine NO eNOS (-) (-) L-Citrulline EDHF(s) Pgl 2 (-) (-) PMN M  Platelet (-) VSMC EC
  6. 6. Imbalance in Factors Affecting Vascular Tone and Structure Nephron destruction and renal failure EDHF= endothelium-derived hyperpolarizing factors ROS= reactive oxygen species EDCF= endothelium-derived constricting factors Angiotensin II Catecholamines Endothelin-1 ROS Cytokines EDCF Nitric Oxide Prostacyclin Bradykinin EDHF Constrictors/ Growth Promoters Dilators/ Growth Inhibitors Vascular tone and structure
  7. 7. ROS Reduces the Biological Effects of NO + = OONO _ (-) Afferent Arteriole L-Arginine NO eNOS L-Citrulline NE VSMC PMN M  Fibroblast EC Mast cell (+) O 2 •
  8. 8. 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
  9. 9. 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
  10. 10. 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 <ul><li>Mechanical stress </li></ul><ul><li>Mesangial changes </li></ul><ul><li>Oxidative stress </li></ul><ul><li>Proteinuria </li></ul><ul><li>NF-  B activation </li></ul>Glomerulosclerosis & Tubulo-interstitial fibrosis Renal disease Nephron loss Adapted from Berk B. 2001.
  11. 11. Angiotensin II Induces Oxidative Stress in the Kidney <ul><li>Stimulation of Membrane NOX-1 Oxidase* </li></ul><ul><ul><li>Increased superoxide (O 2 ) </li></ul></ul><ul><ul><li>Increased thiobarbituric acid reactive substances </li></ul></ul><ul><ul><li>Increased oxidized lipids </li></ul></ul><ul><ul><li>Increased tissue protein carbonyl content </li></ul></ul><ul><li>Induction of Heme Oxidase-1 (HO-1) </li></ul><ul><li>Activation of NF-  B </li></ul><ul><ul><li>Increased inflammatory cytokines </li></ul></ul>*NAD(P)H Oxidase
  12. 12. Renal Sources of ROS <ul><li>NOX-1 oxidase* </li></ul><ul><li>Xanthine oxidase </li></ul><ul><li>Heme oxygenase–1 </li></ul><ul><li>Cyclo-oxygenase </li></ul><ul><li>Lipoxygenase </li></ul><ul><li>Cytochrome P 450 mono-oxygenase </li></ul><ul><li>Mitochondrial oxidative phosphorylation </li></ul>O 2 H 2 O 2 H 2 O+O 2 *NADP(H) oxidase Superoxide dismutase Catalase O 2 •
  13. 13. Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors  O 2 Endothelial Cells and  H 2 O 2 Vascular Smooth Muscle Endothelial Dysfunction Apoptosis Vasoconstriction Leukocyte adhesion Lipid deposition Thrombosis VSMC growth Hypertension Smoking Diabetes LDL Homocysteine Estrogen deficiency
  14. 14. 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
  15. 15. 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
  16. 16. Fibrosis and Nephron Loss: A Renal Response to Injury 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
  17. 17. TGF-  TGF-  plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units
  18. 18. bFGF PDGF Ang II TSP1 TGF-  O 2 • TGF-  plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units O 2 •
  19. 19. TIMP bFGF PDGF Ang II Proteases (-) (-) (+) (+) (+) TSP1 ET-1 PAI-1 O 2 • TGF-  TGF-  plays a key role in extracellular matrix formation in mesangium and interstitium that leads to fibrosis and loss of nephron units O 2 •
  20. 20. 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
  21. 21. Aldosterone Promotes Renal Fibrosis by Multiple Mechanisms Adrenal Vascular Aldosterone PAI-1 Nitric oxide synthesis Na + influx into VSMC Norepinephrine uptake into VSMC Angiotensin II AT1R binding of Ang II Stimulates Inhibits Fibroblast collagen synthesis
  22. 22. 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.

×