Abstract
The aim of this thesis is to increase our knowledge into the immunopathogenesis of renal sterile inflammatory diseases, with a focus on the innate immune response activation by the danger protein S100A8/A9 and the receptor TREM-1.
We found that S100A8/A9 is a pivotal player in renal repair following hypoxic damage, through an immune-regulatory role resulting in the alternative activation of macrophages. By controlling excessive M2 polarization, S100A8/A9 fine-tunes the adaptive response of the kidney to IR-induced AKI (Chapter 2). Conversely, in chronically inflamed kidneys, S100A8/A9 contributes to the development of fibrosis possibly through a direct effect on dedifferentiation and apoptosis in tubular epithelial cells. This effect was independent of S100A8/A9-induced inflammation and recruitment of leukocytes into the kidney (Chapter 3).
Instead, TREM-1 is not involved in the amplification of acute renal damage and inflammation in preclinical model of acute kidney injury. Additionally, renal transplanted patients carrying the TREM1 gene variant p.Thr25Ser do not show any association with pathological consequences after transplantation (Chapter 5). TREM-1, however, limits the maladaptive repair post IR-induced AKI, through a direct effect on tubular epithelial mitochondrial homeostasis and energy production, empowering cell cycle progression. The metabolic advantage provided by TREM-1 is indispensable for tubular proliferation, which sustains renal repair and accelerates the recovery from IR (Chapter 6). In the preclinical model of chronic kidney disease TREM-1 and its adapter molecule DAP12 are not involved in the development of renal fibrosis. DAP12, partly through TREM-1, modulates the renal inflammatory response following unilateral ureteral obstruction (Chapter 7).
We found that S100A8/A9 is a pivotal player in renal repair following hypoxic damage, through an immune-regulatory role resulting in the alternative activation of macrophages. By controlling excessive M2 polarization, S100A8/A9 fine-tunes the adaptive response of the kidney to IR-induced AKI (Chapter 2). Conversely, in chronically inflamed kidneys, S100A8/A9 contributes to the development of fibrosis possibly through a direct effect on dedifferentiation and apoptosis in tubular epithelial cells. This effect was independent of S100A8/A9-induced inflammation and recruitment of leukocytes into the kidney (Chapter 3).
Instead, TREM-1 is not involved in the amplification of acute renal damage and inflammation in preclinical model of acute kidney injury. Additionally, renal transplanted patients carrying the TREM1 gene variant p.Thr25Ser do not show any association with pathological consequences after transplantation (Chapter 5). TREM-1, however, limits the maladaptive repair post IR-induced AKI, through a direct effect on tubular epithelial mitochondrial homeostasis and energy production, empowering cell cycle progression. The metabolic advantage provided by TREM-1 is indispensable for tubular proliferation, which sustains renal repair and accelerates the recovery from IR (Chapter 6). In the preclinical model of chronic kidney disease TREM-1 and its adapter molecule DAP12 are not involved in the development of renal fibrosis. DAP12, partly through TREM-1, modulates the renal inflammatory response following unilateral ureteral obstruction (Chapter 7).
| Original language | English |
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| Qualification | Doctor of Philosophy |
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| Award date | 9 Nov 2018 |
| Print ISBNs | 9789463750622 |
| Publication status | Published - 2018 |
