Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Angiotensin II Type 1 Receptor Antagonist Losartan Inhibits TNF-α Induced Inflammation and Degeneration Processes in Human Nucleus Pulposus Cells

Version 1 : Received: 15 November 2020 / Approved: 17 November 2020 / Online: 17 November 2020 (14:48:38 CET)

How to cite: Saravi, B.; Li, Z.; Pfannkuche, J.; Wystrach, L.; E. Albers, C.; Grad, S.; Alini, M.; Richards, R.G.; Lang, C.; Südkamp, N.; Schmal, H.; Lang, G. Angiotensin II Type 1 Receptor Antagonist Losartan Inhibits TNF-α Induced Inflammation and Degeneration Processes in Human Nucleus Pulposus Cells. Preprints 2020, 2020110456 (doi: 10.20944/preprints202011.0456.v1). Saravi, B.; Li, Z.; Pfannkuche, J.; Wystrach, L.; E. Albers, C.; Grad, S.; Alini, M.; Richards, R.G.; Lang, C.; Südkamp, N.; Schmal, H.; Lang, G. Angiotensin II Type 1 Receptor Antagonist Losartan Inhibits TNF-α Induced Inflammation and Degeneration Processes in Human Nucleus Pulposus Cells. Preprints 2020, 2020110456 (doi: 10.20944/preprints202011.0456.v1).

Abstract

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

Subject Areas

Intervertebral Disc; Renin-Angiotensin-System; Degeneration; Regeneration; Spine; Inflammation

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