Hypertension mechanis-m

Hypertension mechanis-m：28 aa derived from 126 aa precursor；antagonizing the vasoconstrictor actions of AngII。

Hypertension mechanism

• Molecular mechanisms
  • Renin/angiotensin/aldosterone+ANP system
    • JG cells in the kidney can release Renin
      • release of Renin can be stimulated by 2 extracellular paths
        • blood volume decrease directly stimulates JG cells.
        • Sympathetic neurones release Noradrenaline, noradrenaline binds the β-adewnergic receptors on JG cells.
          • This will finally leads to the exocytosis of the renin secretory vesicles.
    • Angiotensinogen is a glycoprotein synthesized by the liver.
    • Renin cleaves angiotensinogen into Ang I (angiotensin I), ACE cleaves ang I into Ang II
      • Here the ACE inhibitor is a hypertension drug
    • Ang II's function
      • Picture
      • Ang II stimulates Vasoconstriction on Arteriole
      • AngII binds to AT1(a GPCR) on zona glomerulosa of the adrenal gland
        • downstream signaling of AT1
          • AT1 -|-> Gq/11 -> phospholipase C --> PKC
            • Details
              • PLC - - PIP2
                • DAG -> PKC
                • IP3 -> Ca2+ release channel -->[Ca2+i] -> PKC
        • zona glomerula will secrects aldosterone apon the stimulation
          • aldosterone affects on ENaCs(a sodium channel) on the cortical collecting duct of the kidney, it results in increase of the Na+ and water uptake to the circulation, and thereby it increases the Blood volume.
            • about ENaCs
              • heterotetramer (α2βγ)
              • A hypertension drug can inhibits ENaCs through binding to its extracellular loop.
              • The intracellular C terminal domain is major sites for the pathogenic mutation of hypertension.
              • Other channels also presents on the duct of the kidney and have similar function with ENaCs, such as NHE1 and NHE3
                • The hyperactivation of them is associated with hypertention
                • They can also be the targets of hypertensive drug
    • ANP's regulation (against AngII+renin)
      • ANP is released by heart
        • 28 aa derived from 126 aa precursor
        • it effects on receptors linked with guanylyl cyclase(GC)
      • ANP's biological effects
        • inhibits adosterone secretion
        • antagonizing the vasoconstrictor actions of AngII
          • cause relaxation of blood vessels
        • inhibits release of renin
        • Suppress fluid and salt intake
  • NO system
    • 1. Endothelial cells express NO synthase
    • 2. Calmodulin activates NO synthase
    • 3. NO synthase synthesis NO
    • 4. NO activates sGC in smooth muscle cells
    • 5. this finally leads to visodilation and the reduce of blood pressure
    • Mechanisms controlling the phosphorylation states of MLC
      • MLC
        • phosphorylation will leads to the contraction
        • dephosphorylation will leads to the relaxation
      • IP3 --> Ca2+ -> Calmodulin -> MLCK +p MLC
      • NO --> cGMP -> cGKI -> phosphatase -p MLC
      • Contractile agonist -> Receptor
        • -|- Ga12/13 -> RhoA-GTP -> ROCK -| MLCP
          • Calcium-independent contraction
        • -|- Gaq --> Ip3 --> Ca2+ -> CaM -> MLCK
• Mutation of genes
  • regulates sodium and water excretion/retention in kidney
  • more than 50 are identified
• Contributions