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.
Highlights
Chronic kidney disease (CKD) is a growing disease burden, predicted to become the fifth global cause of death by 2040 [1]
Failure of serum creatinine to decrease is currently the best early indicator of the acute kidney injury (AKI)-to-CKD transition, but it is still a late event that does not allow the initiating of preventive strategies when AKI is diagnosed
We examine key molecular and cellular mechanisms involved in both maladaptive responses and the endogenous repair mechanisms in the kidney, which offer an opportunity for the design of new therapeutic approaches
Summary
Chronic kidney disease (CKD) is a growing disease burden, predicted to become the fifth global cause of death by 2040 [1]. CKD is associated with an increased risk of CKD progression, death and acute kidney injury (AKI), which is independent from the cause of CKD. A suboptimal array of early diagnostic biomarkers and of effective treatments for AKI or CKD contributes to the increasing global impact of kidney disease. Failure of serum creatinine to decrease is currently the best early indicator of the AKI-to-CKD transition, but it is still a late event that does not allow the initiating of preventive strategies when AKI is diagnosed. This raises the issue of defective kidney repair following AKI and/or a negative impact of prior CKD on kidney repair. We examine key molecular and cellular mechanisms involved in both maladaptive responses and the endogenous repair mechanisms in the kidney, which offer an opportunity for the design of new therapeutic approaches
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