Cell death is a fundamental biological process underlying normal development, homeostasis, and diseases. Regulated cell death is defined as a molecularly controlled cell death that can be modulated (either promoting or preventing) by specific interventions (1). Although apoptosis has been the focus of interest regarding research on regulated cell death and has been historically considered a major cell death pathway in kidney disease processes, there are surprisingly many other ways cells end their lives in a molecularly regulated manner, such as necroptosis, pyroptosis, ferroptosis, and others. Among them, ferroptosis is attracting attention as a critical contributor and a potential novel therapeutic target for many common pathologic states, such as acute and chronic kidney diseases, cardiovascular diseases, neurodegeneration, stroke, chemotherapy-resistant cancers, and more (1, 2).
The term “ferroptosis” was coined in 2012 to describe a distinct form of cell death caused by the pathologic accumulation of toxic lipid peroxides (i.e., oxidized lipids) in an iron-dependent manner (1–3). Accumulation of toxic lipid peroxides worsens the redox status of the cell membrane (ferroptotic stress) and causes plasma membrane damage and subsequent cellular rupture (Figure 1). The glutathione/glutathione peroxidase 4 (GPX4) defense pathway prevents this pathologic consequence by detoxifying toxic lipid peroxides. Ferroptosis is particularly relevant to kidney diseases because the kidney is one of the organs most vulnerable to dysregulation and insufficient activity of GPX4 (4). This was highlighted by examining mice with complete absence (through genetic deletion) of the Gpx4 gene. Mice without the Gpx4 gene had massive albuminuria, kidney tubular epithelial cell death, and subsequent mortality just a few weeks after inducing the gene deletion (4). Moreover, recent human studies suggest the potential involvement of the ferroptotic process in acute kidney injury (AKI) and chronic kidney disease (CKD), highlighting its clinical significance (5–8).
Ferroptosis underlies multiple forms of acute and chronic kidney diseases
Citation: Kidney News 14, 4
Ferroptosis underlies multiple forms of acute and chronic kidney diseases
Citation: Kidney News 14, 4
Ferroptosis underlies multiple forms of acute and chronic kidney diseases
Citation: Kidney News 14, 4
The first investigations of the ferroptotic process in nephrology examined its role in AKI. Ferroptosis inhibitors have been shown to diminish the severity of AKI in multiple preclinical (animal) AKI models such as ischemia-reperfusion injury and folic acid-induced nephropathy (1, 9). Our study further identified how the ferroptotic process involves maladaptive repair after AKI using single-cell transcriptomics, a revolutionizing tool to decipher complex biological and pathological processes at single-cell resolution (10). After ischemic and toxic injuries, proximal tubular cells of the kidney alter their cellular state significantly and acquire a proinflammatory state. They also revert to a more primitive state called dedifferentiation (10–14). The accumulation of these inflammatory proximal tubular cells appears to promote kidney inflammation and a maladaptive repair process (10–14). The ferroptotic process uniquely contributes to this dynamic alteration of the proximal tubule cell state (10). Our group found that ferroptotic stress promotes the accumulation of these inflammatory proximal tubule cells inside the severely damaged kidneys, in addition to triggering ferroptotic death of these cells (Figure 1). Our results, using a mouse model, suggest that inhibiting the ferroptotic process holds the potential to disrupt the AKI to CKD transition.
Although most of the currently available data are derived from animal models, emerging evidence supports the pathogenic role of ferroptosis in multiple forms of CKD. By detailed and integrated analyses of genome-wide association studies on kidney function with multiple human transcriptomic and epigenomic datasets, two genes (DPEP1 and CHMP1A) were identified as potential causal genes of CKD progression (6). This mechanistic study using animal models found that these two genes control cellular ferroptosis sensitivity of proximal tubule cells by regulating cellular iron homeostasis. Ferroptosis is also linked with autosomal dominant polycystic kidney diseases (15). Surprisingly, pharmacological induction of the ferroptotic process increased the cyst growth in Pkd1 null mice by triggering cellular proliferation of cyst-lining epithelial cells in addition to inducing cell death. Conversely, pharmacological inhibition of ferroptosis reduced the cyst size. Clinical and experimental data also show ferroptosis of the neutrophil promotes the pathogenesis of lupus nephritis in mice and likely in humans (7). These data collectively support that ferroptosis inhibition represents an attractive therapeutic strategy to prevent multiple forms of CKD. We also need to be aware that a therapeutic strategy that enhances ferroptosis gains significant attention to treat chemotherapy-resistant cancers, as ferroptosis is identified as a targetable vulnerability of therapy-resistant cancers (16). Therefore, we may see increased AKI incidence due to enhanced tubular toxicity in cancer patients treated with the pro-ferroptotic small molecules as a chemosensitizer in the future.
In summary, elucidating and understanding the molecular nexus that controls ferroptosis sensitivity and resistance in the kidney may provide new therapeutic targets for multiple forms of kidney diseases and may aid in identifying protective adjunctive therapies to prevent or mitigate kidney injury related to cancer therapies.
References
- 1.↑
Maremonti F, et al. Mechanisms and models of kidney tubular necrosis and nephron loss. J Am Soc Nephrol 2022; 33:472–486. doi: 10.1681/ASN.2021101293
- 2.↑
Conrad M, et al. Targeting ferroptosis: New hope for as-yet-incurable diseases. Trends Mol Med 2021; 27:113–122. doi: 10.1016/j.molmed.2020.08.010
- 3.↑
Dixon SJ, et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012; 149:1060–1072. doi: 10.1016/j.cell.2012.03.042
- 4.↑
Friedmann Angeli JP, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16:1180–1191. doi: 10.1038/ncb3064
- 5.↑
Wenzel SE, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 2017; 171:628−641.e26. doi: 10.1016/j.cell.2017.09.044
- 6.↑
Guan Y, et al. A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis. Nat Commun 2021; 12:5078. doi: 10.1038/s41467-021-25377-x
- 7.↑
Li P, et al. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat Immunol 2021; 22:1107–1117. doi: 10.1038/s41590-021-00993-3
- 8.↑
Müller T, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci 2017; 74:3631–3645. doi: 10.1007/s00018-017-2547-4
- 9.↑
Linkermann A, et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA 2014; 111:16836–16841. doi: 10.1073/pnas.1415518111
- 10.↑
Ide S, et al. Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair. Elife 2021; 10:e68603. doi: 10.7554/eLife.68603
- 11.
Kirita Y, et al. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. Proc Natl Acad Sci USA 2020; 117:15874–15883. doi: 10.1073/pnas.2005477117
- 12.
Gerhardt LMS, et al. Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury. Proc Natl Acad Sci USA 2021; 118:e2026684118. doi: 10.1073/pnas.2026684118
- 13.
Lu Y-A, et al. Single-nucleus RNA sequencing identifies new classes of proximal tubular epithelial cells in kidney fibrosis. J Am Soc Nephrol 2021; 32:2501–2516. doi: 10.1681/ASN.2020081143
- 14.↑
Rudman-Melnick V, et al. Single-cell profiling of AKI in a murine model reveals novel transcriptional signatures, profibrotic phenotype, and epithelial-to-stromal crosstalk. J Am Soc Nephrol 2020; 31:2793–2814. doi: 10.1681/ASN.2020010052
- 15.↑
Zhang X, et al. Ferroptosis promotes cyst growth in autosomal dominant polycystic kidney disease mouse models. J Am Soc Nephrol 2021; 32:2759–2776. doi: 10.1681/ASN.2021040460
- 16.↑
Rodriguez R, et al. Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol Cell 2022; 82:728–740. doi: 10.1016/j.molcel.2021.12.001
