Pistorio, Valeria (2021) Unravelling CtsD-cell-specific role in macrophages during tissue remodelling in kidney disease. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Resource language: English
Title: Unravelling CtsD-cell-specific role in macrophages during tissue remodelling in kidney disease
Creators:
CreatorsEmail
Pistorio, Valeriavaleria.pistorio@unina.it
Date: 12 April 2021
Number of Pages: 103
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 33
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
Pavone, LuigiUNSPECIFIED
Moles Fernandez, Ana BelenUNSPECIFIED
Date: 12 April 2021
Number of Pages: 103
Keywords: kidney disease, cathepsin D fibrosis, macrophages
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/10 - Biochimica
Date Deposited: 20 Apr 2021 08:03
Last Modified: 07 Jun 2023 10:34
URI: http://www.fedoa.unina.it/id/eprint/13892

Collection description

Kidney disease is increasingly considered as a global public health issue. Prolonged tissue damage, accompanied by activation of proinflammatory and pro-fibrotic signaling pathways, causes an excess of extracellular matrix (ECM) deposition resulting in renal fibrosis and chronic kidney disease (CKD). Unfortunately, due to the lack of adequate specific treatments, many patients (>2 million worldwide) progress from CKD to end-stage renal disease requiring transplantation. Targeted treatments for kidney disease are not currently available or are mainly limited on managing the underlying cause of the disease. Therefore, it is essential to improve our knowledge about the cellular and molecular drivers controlling kidney disease to find new therapeutic candidates and develop new and more specific drugs for treating CKD. Previous reports about the role of cathepsin D in renal disease are controversial, pointing towards a cell-specific role for this protease in kidney disease progression. Thus, the aim of this project was to elucidate the role of CtsD during progressive kidney disease using a novel conditional knockout mouse model with the specific deletion of the CtsD in macrophages. Macrophage-CtsD sufficient (CtsDΔMyel+/+) and deficient (CtsDΔMyel-/-) mice were used to study in vivo the effects of CtsD deletion in macrophages both in early-stage and chronic kidney disease. Moreover, peritoneal macrophages isolated from macrophage-CtsD sufficient and deficient mice were used to study in vitro the effects of CtsD deletion on macrophage activation and polarization. Our results validate for the first time the CtsDΔMyel-/- mouse strain by demonstrating the CtsD cell-specific deletion in macrophages. Macrophage-CtsD specific deletion in an early-stage kidney disease model (unilateral ureteral obstruction, UUO, 5 days) caused a decrease of kidney inflammation and number of total macrophages as well as an impaired M2 macrophage polarization. However, these changes did not translate into an alteration of kidney damage. On the other hand, the absence of CtsD in macrophages during chronic kidney disease (UUO 10 days) resulted in an increased kidney fibrosis with no changes in tubular cell damage or inflammation. Our in vitro results, using isolated peritoneal macrophages, proved that the enhanced ECM accumulation and renal fibrosis, observed in the macrophage-CtsD deficient mice, were the consequence of a deficient proteolytic enzyme profile and of an impairment in lysosomal degradation of collagen. In summary, our results provide novel experimental evidence of the fundamental role played by CtsD in driving collagen recycling and controlling proteolytic enzymes during chronic renal injury. This information might be essential when considering long-term therapies based in CtsD inhibition during progressive kidney disease.

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