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Review
. 2021 Mar 15;10(3):650.
doi: 10.3390/cells10030650.

The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

Babak Saravi  1   2 , Zhen Li  1 , Corinna N Lang  3   4 , Bonaventura Schmid  5 , Frauke K Lang  6 , Sibylle Grad  1 , Mauro Alini  1 , Robert Geoffrey Richards  1 , Hagen Schmal  2   7 , Norbert Südkamp  2 , Gernot M Lang  2
Affiliations
Review

The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis?

Babak Saravi et al. Cells. .

Abstract

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.

Keywords: COVID-19; RAS; cardiovascular; inflammation; intervertebral disc; regeneration; renin-angiotensin; senescence; vulvodynia.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Tissue renin-angiotensin system in humans. Local renin-angiotensin systems are found in numerous human tissues, including skeletal muscle, bone, cardiovascular, brain, and intervertebral disc (IVD) tissue. The angiotensin II receptor type 2 (AGTR2) and the Ang1–7/Mas receptor (MasR) axis counteract the pro-inflammatory effects (increasing intracellular reactive oxygen species (ROS) of accumulating angiotensin II concentrations (AngII) on angiotensin II receptor type 1 (AGTR1). Chronic/degenerative disease states are characterized by the domination of the pathological tRAS pathway (angiotensin-converting enzyme (ACE)/AngII/AGTR1) over the protective axis (AGTR2/ACE2/Ang1–7/MasR), and aging might shift the balance between protective and pathological RAS axis towards AGTR1/ACE/AngII [2,3].
Figure 2
Figure 2
SARS-CoV 2 interactions with tRAS. SARS-CoV-2 binding on ACE2 inhibits the conversion of the pathological AngII to protective Ang1–7. The resulting increase in local angiotensin 2 (AngII) concentrations lead to an overactivation of the pathological AngII/angiotensin II receptor type 1 (AGTR1) axis, leading to a cytokine storm and resulting in overwhelming inflammatory reactions [169].
See this image and copyright information in PMC

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