Acute kidney injury (AKI) is a common condition that is characterized by necrosis of certain renal tubular cells, particularly in the proximal tubule, as well as modification of cellular signaling in remaining tubular cells to promote tissue repair. Nonetheless, the clinical context, severity, and duration of AKI may contribute to irreversible kidney parenchymal damage and fibrosis, which ultimately leads to chronic kidney disease. At the cellular level, evidence of failed proximal tubule repair includes persistent expression of markers such as the hepatitis A virus cellular receptor (Havcr1), keratin 20 (Krt20), and/or the vascular cell adhesion molecule 1 (Vcam1) (1). Therefore, an area of considerable interest is the identification of protective cellular signatures during AKI.
In a recent issue of Kidney International, Cuarental et al. (2) used proximal tubule cell models as well as rodent models of AKI to identify a significant and consistent upregulation of Fosl1 during the early phase of kidney injury. Fosl1 is a leucine zipper protein that forms part of the canonical activator protein-1 transcription factor complex. The authors demonstrated that Fosl1 is abundant in the proximal tubule cells and can bind directly to the α-klotho gene to promote its expression. To study the relevance of Fosl1 during AKI, the authors selectively deleted Fosl1 in the proximal tubule. Compared with wild-type (WT) mice, Fosl1-deficient mice had more severe kidney injury after exposure to either cisplatin or folic acid, which is consistent with a protective role of FosI1 during AKI. As would be predicted, mice lacking Fosl1 also had lower expression and levels of α-klotho during AKI compared with WT mice. Treatment with exogenous α-klotho ameliorated the kidney injury produced by cisplatin or folic acid in mice lacking Fosl1, supporting a pathobiological mechanism by which Fosl1 exerts its protective functions upstream of α-klotho.
These results provide a novel, direct link to previous observations that α-klotho reduction contributes to incidence and progression of AKI. α-Klotho has important functions in the kidney as a mediator of fibroblast growth factor 23 actions and systemically as a pleiotropic protein with anti-aging, anti-fibrotic, and antioxidant properties. The study by Cuarental et al. (2) provides key insights into the protective role of increased proximal tubule Fosl1 as an adaptive response during AKI via upregulation of α-klotho. Overall, this study underpins a new strategy for α-klotho-centered therapeutics in AKI that requires further translational investigation.
Conceptual impact of Fosl1-Klotho adaptive response in AKI
Citation: Kidney News 15, 6
During AKI, several proinflammatory responses are upregulated, here illustrated by an increase in tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1). The inflammatory response contributes to cellular injury and also to a decrease in α–klotho. Protective cellular responses during AKI include the upregulation of Fosl1, which via an increase in a–klotho expression ameliorates cellular injury. Deletion of Fosl1 results in more severe downregulation of α–klotho and cellular injury. The visual abstract was created with BioRender.com.Conceptual impact of Fosl1-Klotho adaptive response in AKI
Citation: Kidney News 15, 6
During AKI, several proinflammatory responses are upregulated, here illustrated by an increase in tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1). The inflammatory response contributes to cellular injury and also to a decrease in α–klotho. Protective cellular responses during AKI include the upregulation of Fosl1, which via an increase in a–klotho expression ameliorates cellular injury. Deletion of Fosl1 results in more severe downregulation of α–klotho and cellular injury. The visual abstract was created with BioRender.com.Conceptual impact of Fosl1-Klotho adaptive response in AKI
Citation: Kidney News 15, 6
During AKI, several proinflammatory responses are upregulated, here illustrated by an increase in tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1). The inflammatory response contributes to cellular injury and also to a decrease in α–klotho. Protective cellular responses during AKI include the upregulation of Fosl1, which via an increase in a–klotho expression ameliorates cellular injury. Deletion of Fosl1 results in more severe downregulation of α–klotho and cellular injury. The visual abstract was created with BioRender.com.References
- 1.↑
Gerhardt LMS, et al. Lineage tracing and single-nucleus multiomics reveal novel features of adaptive and maladaptive repair after acute kidney injury single-cell multiomics of AKI responses. J Am Soc Nephrol 2023; 34:554–571. doi: 10.1681/ASN.0000000000000057
- 2.↑
Cuarental L, et al. The transcription factor Fosl1 preserves Klotho expression and protects from acute kidney injury. Kidney Int 2023; 103:686–701. doi: 10.1016/j.kint.2022.11.023
