Exogenous Klotho Extends Survival in COVID-19 Model Mice
Abstract
:1. Introduction
- Klotho is the obligate co-receptor for FGF23, which is an important phosphaturic hormone [20]. Consistently with this, it is considered that FGF23 phosphaturic actions are critically dependent on Klotho [14]. Moreover, it has been considered that Klotho may have FGF23-independent phosphaturic effects [25].
- Klotho and TGF-β: Klotho at least partially protects against fibrosis by preventing TGF-β binding to its receptor and initiating a cascade [22].
- Klotho and Nrf2 pathway: Nfr2 is a transcription factor that controls responses to oxidative stress, and as such is an antioxidant pathway. It is activated by Klotho [21].
2. Materials and Methods
2.1. Animal Use Disclosure
2.2. Materials and Methods for the First Animal Study
2.3. Materials and Methods for the Second Animal Study
2.4. Mice with Osmotic Minipump Implants
2.5. Mice Receiving Intraperitoneal Injections
2.6. Statistical Methods
3. Results
3.1. General Description
3.2. Survival Analysis: Kaplan–Meier
3.3. Survival Analyses: Cox and Weibull Models
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Risk Factor | Role or Correlation of Klotho | Ref. |
---|---|---|
Advanced age | Low Klotho is associated with shorter lifespan Serum Klotho decreases substantially with aging Aging is the strongest risk factor in COVID-19 | [4,37] |
Chronic kidney disease (CKD) | Main cause of systemic pan-Klotho deficiency Most potent risk factor for COVID-19 mortality after advanced age and cancer Klotho deficiency worsens CKD progression and induces the premature aging phenotype of CKD | [3,4,6,7,12] |
Diabetes mellitus (DM) | KL is downregulated in type 2 DM DM (especially uncontrolled DM) is a risk factor for COVID-19 mortality | [4,35] |
Obesity | Serum Klotho is decreased in obesity Obesity is a risk factor for COVID-19 mortality | [4,38] |
Cancer | Klotho has been identified as a tumor suppressor through modulation of IGF-1 Cancer is a strong risk factor for COVID-19 mortality | [4,36] |
Complication | Role or Correlation of Klotho | Ref. |
---|---|---|
Acute kidney injury (AKI) | AKI induces a dramatic decrease in systemic Klotho levels and a status of pan-Klotho deficiency AKI is one of the most serious complications associated with mortality in COVID-19 The viral tropism in kidney is 100-fold greater than in lung tissue | [5,39,47] |
Acute respiratory distress syndrome (lung-kidney axis) | AKI has a strong temporal association with respiratory failure and mechanical ventilation Klotho administration alleviates lung injury induced by kidney injury in animal models Klotho is a strong causal candidate underlying the lung-kidney axis, which is described in COVID-19 disease | [40,41,48] |
(Micro) thrombosis | PAI-1 levels, a key molecule in thrombosis, are strikingly elevated in Kl deficient mice PAI-1 contributes to the aging phenotype as an important mediator of senescence COVID-19 induces a prothrombotic state according to meta-analysis | [49,50,51] |
Cytokine release syndrome | IL-6 plays a key role in cytokine release syndrome Klotho downregulates endothelial IL-6 expression Klotho alleviates inflammation via modulation of Wnt1/pCREB pathway SARS-CoV-2 infection can induce cytokine release syndrome | [52,53] |
Cognitive disorder | Klotho depletion in the choroid plexus induces inflammation and immune-mediated neuropathogenesis Kl overexpression enhances cognition in mice and nonhuman primates Klotho depletion impairs memory COVID-19 is associated with impairment in executive functioning | [42,43,46,54,55] |
Multi-organ failure | Sepsis creates a state of Klotho deficiency in ICU patients, especially in the context of AKI Low Klotho levels correlate with major adverse kidney events in humans Pretreatment with recombinant Klotho alleviates organ damage and inflammation in rodent models with endotoxemia | [44,56,57] |
a | ||||
---|---|---|---|---|
Mouse Number | Group | Baseline Age | Baseline Temperature | Baseline Weight |
1 | Control | 8 weeks | 37.4 | 19.5 |
2 | Control | 8 weeks | 37.2 | 19 |
3 | Control | 8 weeks | 37.4 | 20.5 |
4 | Control | 8 weeks | 37.6 | 20 |
5 | Control | 8 weeks | 36.9 | 19.5 |
6 | Mouse Klotho | 8 weeks | 37.1 | 20 |
7 | Mouse Klotho | 8 weeks | 38.1 | 21.5 |
8 | Mouse Klotho | 8 weeks | 37.3 | 21.5 |
9 | Mouse Klotho | 8 weeks | 37.2 | 19.5 |
10 | Mouse Klotho | 8 weeks | 37.4 | 18.5 |
11 | Human Klotho | 8 weeks | 37.4 | 18 |
12 | Human Klotho | 8 weeks | 37.4 | 19.5 |
13 | Human Klotho | 8 weeks | 37.8 | 21.5 |
14 | Human Klotho | 8 weeks | 37.2 | 19.5 |
15 | Human Klotho | 8 weeks | 37.0 | 19.5 |
b | ||||
Variable | Kruskal Wallis p value | |||
Weight | 0.645 | |||
Temperature | 0.989 |
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Alem, F.; Campos-Obando, N.; Narayanan, A.; Bailey, C.L.; Macaya, R.F. Exogenous Klotho Extends Survival in COVID-19 Model Mice. Pathogens 2023, 12, 1404. https://doi.org/10.3390/pathogens12121404
Alem F, Campos-Obando N, Narayanan A, Bailey CL, Macaya RF. Exogenous Klotho Extends Survival in COVID-19 Model Mice. Pathogens. 2023; 12(12):1404. https://doi.org/10.3390/pathogens12121404
Chicago/Turabian StyleAlem, Farhang, Natalia Campos-Obando, Aarthi Narayanan, Charles L. Bailey, and Roman F. Macaya. 2023. "Exogenous Klotho Extends Survival in COVID-19 Model Mice" Pathogens 12, no. 12: 1404. https://doi.org/10.3390/pathogens12121404
APA StyleAlem, F., Campos-Obando, N., Narayanan, A., Bailey, C. L., & Macaya, R. F. (2023). Exogenous Klotho Extends Survival in COVID-19 Model Mice. Pathogens, 12(12), 1404. https://doi.org/10.3390/pathogens12121404