## 4 Discussion
### The Tissue renin-Angiotensin System: AngII as a Pro-Inflammatory and Catabolic Hormone  
The renin-angiotensin system (RAS) has an important role in the regulation and progression of tissue injuries in the cardiovascular system [41]. In earlier studies, a variety  
Figure 6: Influence of angiotensin II type 1 receptor (AGTR1) inhibition on secreted IL-6 levels in human NP cells after 72 h of exposure. The results are shown as the original concentrations in pg/mL in the media without normalization. Data from two donors assessed in triplicate are shown (\(n=6\)); ***\(p<0.001\); ***\(p<0.0001\). of locally acting renin-angiotensin system components were identified in various human tissues, such as bone, gastrointestinal tract, skin, kidney, and liver, revealing an important role in degenerative and inflammatory processes [42, 43]. AngII, a well-known classical vasoconstrotricory cardiovascular hormone and part of the pathological arm of the tRAS, was also demonstrated to be produced in inflammatory cells, inducing nerve growth and axon sprouting [44, 45, 46, 47, 48]. For the first time, [PERSON] et al. and [PERSON] et al. revealed the existence of local renin-angiotensin systems and their contribution to inflammation in the musculoskeletal system of rats [20, 49]. Recent evidence underlines the statement that the RAS and its main effector, AngII, may be considered as a locally acting system, regulating tissue homeostasis and regeneration, especially in the cardiovascular and nervous systems [50]. Furthermore, AngII induces the expression of pro-inflammatory markers, such as IL-6, TNF-\(\alpha\), and adhesion molecules, and functions as a true pro-inflammatory mediator that regulates inflammation, growth, and fibrosis [51, 52, 53, 54, 55]. In our previous work, we confirmed the existence of AngII and other tRAS components in tissue samples of degenerated discs by immunohistochemistry and gene expression analysis [16]. Disc tissue samples that expressed more tRAS factors showed significantly higher gene expression levels of pro-inflammatory (TNF-\(\alpha\) IL-6) and catabolic genes (ADAMTS 4 and 5), indicating that tRAS contributes to the inflammatory processes operant in IDD. These findings are supported by the fact that the gene expression of NP phenotype-modulating factors, such as ACAN and COL2, was reduced in increased tRAS component-expressing discs. Furthermore, disc tissues with highly positive tRAS expression revealed lower glycosaminoglycan (GAG)/DNA ratios, implying the accelerated state of catabolism due to IDD. Our present work indicates that AngII has the potential to affect IVD matrix degradation as the inhibition of its receptor, AGTR1, led to significant changes in the gene expression of relevant extracellular matrix genes. The roles of ACE and AGTR1 in inflammatory cell processes have previously been shown in synovium tissues from RA patients [20, 56, 57]. Recent research supports our work, revealing increased tRAS activity in the synovial fluid and tissues of patients with RA [58, 59, 60]. [PERSON] and coworkers analyzed the protective potential of losartan in rats with RA [20]. Chronic joint inflammation was induced by intraarticular and periarticular injection of [PERSON]'s complete adjuvant of heat-killed _Mycobacterium tuberculosis_ into the knee joint. Acute joint inflammation was induced by intraarticular injection of \(\lambda\)-carrageenan and kaolin. Western blot analysis and immunohistochemistry reflected the elevated concentrations of AngII protein and AGTR1 in synovium from animals with acute and chronic joint inflammation. Losartan substantially reduced joint swelling and suppressed TNF-\(\alpha\) generation in a dose-dependent manner. [PERSON] et al. investigated the impact of AngII stimulation with different concentrations in rat annulus fibrosus cells by qRT-PCR [49]. Stimulation of rat IVD cells with AngII increased the mRNA expression of ADAMTS-5 significantly, indicating extracellular matrix degradation.