Unravelling CtsD-cell-specific role in macrophages during tissue remodelling in kidney disease

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 ...