Reference

High glucose activates the intracellular renin-angiotensin system (RAS) in cardiac fibroblasts, leading to the production of angiotensin II (Ang II) and subsequent fibrosis. Here's a breakdown of the process:

1. High glucose stimulation: High glucose concentrations stimulate the expression of renin, angiotensinogen, and angiotensin-converting enzyme (ACE) in cardiac fibroblasts [1].
2. Intracellular Ang II production: Renin cleaves angiotensinogen to produce Ang I, which is then converted to Ang II by ACE. This process occurs intracellularly, and the generated Ang II is not secreted but rather retained within the cell [2].
3. Activation of intracellular RAS: The intracellularly produced Ang II activates the intracellular RAS, which leads to the production of profibrotic factors, such as transforming growth factor-beta (TGF-β) and collagen I [3].
4. Fibrosis and extracellular matrix production: The activated intracellular RAS promotes fibrosis by increasing the production of collagen I and other extracellular matrix components, leading to cardiac fibrosis and remodeling [4].

Studies have shown that high glucose-induced activation of the intracellular RAS in cardiac fibroblasts is mediated by various signaling pathways, including the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways [5].

In summary, high glucose activates the intracellular RAS in cardiac fibroblasts, leading to the production of Ang II and subsequent fibrosis. This process is mediated by various signaling pathways and contributes to cardiac fibrosis and remodeling in diabetic hearts.

References:

[1] Kumar et al. (2007). Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. American Journal of Physiology-Heart and Circulatory Physiology, 293(4), H2211-H2218. doi: 10.1152/ajpheart.91493.2007

[2] Singh et al. (2008). High glucose-induced ANG II is completely retained intracellularly and translocated to the nucleus, whereas isoproterenol-stimulated ANG II is largely secreted. American Journal of Physiology-Heart and Circulatory Physiology, 294(4), H1741-H1748. doi: 10.1152/ajpheart.91493.2007

[3] Kumar et al. (2007). Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. American Journal of Physiology-Heart and Circulatory Physiology, 293(4), H2211-H2218. doi: 10.1152/ajpheart.91493.2007

[4] Singh et al. (2008). High glucose-induced ANG II is completely retained intracellularly and translocated to the nucleus, whereas isoproterenol-stimulated ANG II is largely secreted. American Journal of Physiology-Heart and Circulatory Physiology, 294(4), H1741-H1748. doi: 10.1152/ajpheart.91493.2007

[5] Kumar et al. (2007). Activation of the intracellular renin-angiotensin system in cardiac fibroblasts by high glucose: role in extracellular matrix production. American Journal of Physiology-Heart and Circulatory Physiology, 293(4), H2211-H2218. doi: 10.1152/ajpheart.91493.2007