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Updated: Oct 6, 2025
A Large Animal Model for Acute Kidney Injury by Temporary Bilateral Renal Artery Occlusion
Published on: February 2, 2021
Mechanisms and Models of Kidney Tubular Necrosis and Nephron Loss
Francesca Maremonti1, Claudia Meyer1, Andreas Linkermann1,2
1Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
Abstract:
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
Insights
A molecular switch determines if kidney damage leads to regeneration or chronic kidney disease (CKD). Understanding this switch and the inflammatory response to tubular necrosis is key for new therapies.
Area of Science:
- Nephrology
- Cell Biology
- Immunology
Background:
- Chronic kidney disease (CKD) progression is linked to nephron loss.
- Renal tubular cell death occurs via apoptosis in normal processes, but ferroptosis and necroptosis are implicated in acute kidney injury (AKI) and its transition to CKD.
- Necroinflammation, an inflammatory response to necrotic cell death, differs between ferroptosis and necroptosis, impacting tissue response.
Purpose of the Study:
- To investigate the mechanisms of cell death propagation during tubular necrosis.
- To identify a molecular switch that determines nephron regeneration versus nephron loss after tubular necrosis.
- To understand the role of inflammation and inflammatory cells in tubular necrosis and subsequent fibrosis.
Main Methods:
- Review of existing literature on renal cell death pathways (ferroptosis, necroptosis, apoptosis).
- Analysis of morphological descriptions of tubular necrosis.
- Conceptual framework development for a molecular switch governing regeneration vs. loss.
Main Results:
- Cellular mechanisms of ferroptosis and necroptosis are increasingly understood, but their propagation during tubular necrosis remains unclear.
- A molecular switch downstream of tubular necrosis is proposed to dictate nephron fate.
- Inflammatory responses to tubular necrosis, including stimulation of myofibroblasts, are critical factors.
Conclusions:
- Understanding the molecular switch and inflammatory responses to tubular necrosis is crucial for preventing CKD progression.
- Targeting this switch and associated inflammation may offer novel therapeutic strategies for kidney injury.
- Further research into the interplay between cell death, inflammation, and regeneration is needed.
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