## 4 Discussion
### Anti-Inflammatory Therapies Via RAS Inhibition--A Potential Target in IDD? Recent data consistently show that ARBs and ACE-inhibitors have anti-inflammatory effects in various human tissues and show beneficial effects in inflammatory musculoskeletal diseases [21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 61]. [PERSON] and coworkers demonstrated that oral administration of ACE inhibitors in mice reduced TNF-\(\alpha\) release, though high concentrations were needed to reach a meaningful effect [18]. Further, RAS inhibitors abolished LPS-induced high IL-6 and TNF-\(\alpha\) gene expression levels in the kidney [62]. Renal AngII is a key factor in mediating various components of the immune and inflammatory responses and acts as a pro-inflammatory agent [55, 63]. This suggests that the administration of RAS inhibitor in therapeutic dosages to humans with hypertension may also suppress cytokine levels. The angiotensin-converting enzyme inhibitor Enalapril inhibits AngII synthesis from AngI and may suppress pro-inflammatory cytokine production, as previously shown in vitro [64,65]. Captopril, an ACE-inhibitor, is also known to have antirheumatic effects comparable to D-penicillamine [21,66,67]. Therefore, Captopril was considered a valuable drug in patients with hypertension and RA, especially due to the favorable benefit/risk ratio as Captopril lacks serious side effects [67]. [PERSON] et al. demonstrated that losartan suppresses the expression of IL-6, IL-22, IL-17F, and IFN-\(\gamma\) in Peripheral Blood Mononuclear Cells (PBMCs) from RA patients, suggesting that losartan could be a superior option for hypertension treatment in RA patients [68]. Our results reflect previous findings that found downregulations of inflammatory markers in inflammatory cell culture models after AGTR1 blockade or knockdown [69,70]. In contrast to our experiments, these studies used lipopolysaccharidesaccharides to stimulate inflammation in the respective cell cultures and might not be fully comparable. However, our workgroup recently validated the superior potential of TNF-\(\alpha\)-induced inflammatory cell culture models to examine degenerative disc diseases [14]. Further, we showed for the first time that PPAR\(\gamma\) pathway stimulation through losartan has protective effects on human NP cells. Losartan seems to exhibit at least some of its effect through the PPAR\(\gamma\) pathway as the inhibition of PPAR\(\gamma\) partly diminished the protective effects of losartan on the gene expression level. In accordance with the present results, several studies reported that losartan could get internalized through the AGTR1 receptor and act as a partial PPAR\(\gamma\) agonist [69,71,72]. Noticeably, the PPAR\(\gamma\) effects of ARBs might be too small regarding the reachable tissue levels to exert a significant anti-inflammatory effect. Therefore, new drug delivery methods and the development of new ARBs with more potent PPAR\(\gamma\) activation properties or other PPAR\(\gamma\) agonists might be needed if PPAR\(\gamma\) stimulation is the target [73]. PPAR\(\gamma\) activation properties of ARBs can be more seen as a beneficial effect in addition to the inhibition of the pathological tRNAs arm (ACE/AngII/AGTR1 axis). Overall, more details about the interactions of the tRAS, PPAR\(\gamma\) pathway, and ARBs in human IVD cells are warranted in the future. Interestingly, the inhibition of AGTR1 receptors through losartan reduced TNF-\(\alpha\)-induced ACE and AGTR1 upregulation. The upregulation of ACE through AGTR1 was already shown before by [PERSON] et al. [74]. They also could inhibit this upregulation through losartan addition, which concurs with our data. Notably, as seen in our data, the inflammatory environments stimulate ACE and AGTR1 expression, indicating stimulation of the pathological arm of the tRAS in inflammatory settings. This was also shown by [PERSON] et al., who suggested a previously unknown cross-talk between the TNF-\(\alpha\) and the tRAS [75].