Molecular Mechanisms of Kidney Injury and Repair

Abstract

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.

Keywords: acute kidney injury; cell death; chronic kidney disease; kidney; molecular mechanisms; regeneration; treatment.

Figure 1

Mechanisms of kidney injury and repair.

Figure 2

Principal hallmarks of senescent cells. Many different stimuli may cause a DNA damage in the cell and activate the DNA-Damage Response (DDR), which may produce the expression of the Cell-Cycle Arrest (CCA) molecules. Prolonged activation of DDR and CCA proteins produce cellular senescence and the release of the Senescent-Associated Secretory Phenotype (SASP), enriched in different proinflammatory, profibrotic and growth factors that are regulated by NF-κB pathway activation and may cause activation of cellular senescence in a paracrine manner, inflammaging and fibrosis in the kidney, and other tissues.

Figure 3

Glomerulonephritis characterized by a fibrous structure formation (crescent) in renal corpuscle. Glomerular PECs (cytokeratin+) are the main actors, infiltrating cells such as macrophages (CD68+) in crescent formation during rapid progressive glomerulonephritis/crescentic glomerulonephritis (RPGN/CGN). Activated PECs (CD44+/cytokeratin-) invade the glomerular urinary space and obstruct the urinary space. PEC “activation” implies a phenotypic change that promotes their abnormal proliferation and their migration towards the urinary space of renal corpuscles.