Cell-specific role of ADAM10 and ADAM17 in acute and chronic kidney inflammation

• Zellspezifische Rolle von ADAM10 und ADAM17 bei akuter und chronischer Nierenentzündung

Wozniak, Justyna; Panstruga, Ralph (Thesis advisor); Ludwig, Andreas (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) account for about 3 million deaths per year and are therefore classified as a substantial burden with high mortality and enormous financial and social costs. Caused by a variety of different pathologies and closely related to each other, they require a precise anamnesis and, when treated, a sound knowledge of the cellular processes within the different conditions. Common to all pathologies is the inflammation caused by various factors. Inflammation describes a wide range of physiological and pathological processes and cannot be considered a benign or malignant situation per se. Acute inflammation can be seen as a response of the innate and adaptive immune system to a harmful stimulus, including pathogens and damaged cells due to injury, toxic agents or irradiation. Persisting noxae induce a progression towards chronic inflammation. Although most mechanisms induced in acute inflammation are further involved in the chronic state, cell composition differs, resulting in overshooting repair mechanisms accompanied by fibrosis and tissue damage.These processes are orchestrated by a variety of proteins including the ADAM proteases. ADAM10 and ADAM17 are considered as the key sheddases for pro-inflammatory proteins, and while ADAM17 has already been shown to be involved in the progression of nephritis and fibrosis, data for ADAM10 is less available. For this purpose, the involvement of ADAM10 in renal inflammation and chronic kidney disease was investigated in this thesis. The murine model of unilateral ureter obstruction (UUO) has been established and the correct setup of controls concerning the Cre-loxP system and the genetic background of the animals was analysed. Unexpectedly, animals floxed for Adam10 showed a stronger fibrotic reaction post UUO. There are several explanations for the different fibrotic responses, and although this difference should not occur, it does show an influence of ADAM10 on the regulation of inflammation and fibrosis in the kidney. To remedy the problem a revitalisation of the individual lines was carried out. However, the resulting animals could not be studied in this thesis. Therefore, and to investigate the influence of ADAM10 in a different approach, the small molecule inhibitor GI254023X was used. The use of GI254023X in the renal fibrosis model of UUO showed no effect on the strength of fibrosis induction. Nevertheless, in vitro results indicate that ADAM10 and ADAM17 are involved in the TGF β induced induction of α smooth muscle actin in murine fibroblasts. Thus, the inhibitor, once adapted, could still be a promising drug that could prove useful in treating inflammation and the resulting fibrotic response.