Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease
Abstract
:1. Introduction
2. Klotho and Chronic Kidney Disease
2.1. Chronic Kidney Disease
2.2. Klotho in Chronic Kidney Disease
2.2.1. Klotho and FGF-23
2.2.2. Klotho/FGF/PTH Axis
2.2.3. CKD and Cardiovascular Disease
2.2.4. Klotho and Inflammation
2.2.5. Klotho and Fibrosis
3. Acute Kidney Injury
3.1. Klotho in Acute Kidney Injury
3.1.1. Klotho, Inflammation and AKI
3.1.2. Klotho and Non-Inflammatory Mechanisms in AKI
4. Therapeutic Potential of Klotho in Acute and Chronic Kidney Diseases
- (a).
- DNA methyltransferase inhibitor: In regard to the DNA methyltransferase inhibitor azacytidine, it has been observed that Klotho’s promoter is located in a region rich in cytosine and guanine—a CpG island [206,207] that lacks sequences for classic regulatory elements in this region [206]. Azacytidine, in turn, is able to promote an augmentation in the promoter activity of the Klotho gene, leading to a rise in the levels of this protein in cells. The use of this compound in vivo, though, is difficult and regards future research due to the variety of possible activities presented by this compound [2].
- (b).
- Agonists for PPAR-γ: Moving on to troglitazone and ciglitazone, these drugs are classified as thiazolidinediones and they act as agonists of peroxisome proliferator-activated receptor gamma (PPAR-γ) [208]. One study indicated that, in cells from medullary collecting ducts, proximal tubules and distal tubules, there is an induction of the expression of Klotho genes by these compounds, both in a time- and dose-dependent manner. The same study proposed that the activation of this receptor is, then, a potential mechanism for the effect observed, since a selective PPAR-γ antagonist abolished the process [208]. In regard to the clinical use of these molecules, the challenges involve edema, weight gain and osteoporosis, among others [209].
- (c).
- Histone deacetylase inhibitors: The other approach discussed in Figure 4 is the use of histone deacetylase inhibitors, such as trichostatin A and valproic acid. Data indicate that in cells treated with these compounds, the reduced expression of Klotho induced by TWEAK or TNF-α is prevented [110]. Likewise, an increase in Klotho’s gene expression in some cell lineages has been reported [206]. In spite of the fact that these inhibitors are being evaluated in clinical trials involving the treatment of cancer, for example, their use in vivo is still difficult, because of adverse reactions, especially cardio-toxicity [210].
- (d).
- RAAS inhibitors: Regarding the use of RAAS inhibitors, in turn, it has been demonstrated in a rodent model of chronic nephropathy that the inhibition of angiotensin II type 1 receptor with the use of losartan results in an augmentation in Klotho expression, along with a reduction in kidney histological damage [211]. A meta-analysis of randomized controlled trials and systematic reviews, however, has shown that in order to improve some functional parameters in CKD patients, such as blood pressure control and the reduction of proteinuria, dual blockade of RAAS is better than monotherapy [212]. Thus, although the previously discussed alternative represents a potential strategy for the treatment of CKD, the approach itself does not diminish the development of ESKD, for example, so it does not cause a long-term amelioration in the treatment of CKD, as reviewed by that group [212].
- (e).
- Paricalcitol: As illustrated in Figure 4, other compounds are interesting for the elevation of Klotho levels, such as vitamin derivatives, such as paricalcitol. In a study with uremic rats, conducted by Ritter, it was demonstrated that paricalcitol blocks the reduction of Klotho mRNA and protein levels in renal tubules [213]. In another study, on the other hand, an increase in Klotho levels in the kidneys was not observed [214]. Currently, there is a lack of information in the literature in regard to the influence of paricalcitol and other agonists for vitamin D receptors on CKD progression and cardiovascular risk [215]. Furthermore, a meta-analysis highlighted the necessity of future randomized trials to assess the effects of paricalcitol on ESKD progression and mortality in individuals, although some data point out that this approach is effective in the reduction of proteinuria [216]. Moreover, the authors reported that there was a trend towards hypocalcemia in patients [216]. Thus, the clinical feasibility of this approach still needs further studies.
- (f).
- Intermedin: In regard to intermedin, a study with rats with CKD has shown that the decrease in Klotho protein levels was overturned by intermedin in the kidneys, plasma and calcified aorta [217]. This compound also diminished vascular calcification in this animal model [217]. Intermedin, then, could be a promising strategy to increase Klotho levels. However, the lack of information in literature about this compound is a downside of it. Only two experimental papers were found when we searched for information about intermedin and Klotho in Pubmed [217,218]. Thus, further studies are needed in order to shed light on the efficacy and safety of intermedin and on how exactly it is related to Klotho levels.
- (g).
- Statins: Statins have also been proposed as a promising approach to promote Klotho overexpression. Studies with rodents demonstrated that these drugs led both to an increase in renal Klotho levels and to the attenuation of the reduction of Klotho in nephropathy [219]. Furthermore, there was an improvement in the resistance to oxidative stress in CKD [219]. Although the use of statins for patients with correct medical recommendations is considered acceptable because of their benefits [220], a review has pointed out that genetic testing of transporter genes which affect the internalization or efflux of statins would be interesting, considering the existent polymorphisms that can affect both the safety and efficacy of statins, since this genetic background might interfere in the incidence of myopathy and statins results in patients [221].
- (h).
- Recombinant protein: The administration of recombinant Klotho, in turn, is a potential strategy to increase its levels [48]. Studies with rodent models for kidney diseases have shown the attenuation of renal fibrosis [177], the avoidance of progression from AKI to CKD, cardiac remodeling and an improvement in renal and cardiac parameters [177]. Researchers have also observed the reduction of kidney damage and recovery from AKI [46]. However, the Klotho protein’s instability in urine and blood [222] might demand alternatives to an effective recombinant protein administration [223]. Timing for treatment should also be analyzed so that there would not be an impaired recovery of the kidneys [223].
- (i).
- Adenoviral delivery: Lastly, as described in Figure 4, adenoviral delivery of Klotho leads to an increase in this protein level. Studies with rodents with reduced Klotho expression have indicated the mitigation of renal damage promoted by adenoviral Klotho delivery, seen, for example, with a decrease in tubular atrophy [224]. Regarding this approach, there are also other studies involving rodent models for diabetic kidney disease (DKD) that show the amelioration of the disease after the delivery of Klotho, which might be associated with the inhibition of RAAS activation and the Wnt/β-catenin pathway [225] and the improvement of creatinine clearance, proteinuria and tubulointerstitial damage in animals with Ang-II infusion [226]. Moreover, in rodent models for AKI studies have demonstrated the mitigation of histological damage and apoptosis and the improvement of serum creatinine levels post-injury after Klotho delivery [183]. Although promising results have been achieved so far, it is important to mention that the adeno-viral delivery of genes requires caution, due to possible mutagenesis or immunogenicity [227].
- (j).
- Mesenchymal stem cells and extracellular vesicles: Taking into account all the approaches discussed previously, we decided to explore the potential of MSCs due to their applicability in regenerative medicine. Currently, these are the most studied type of stem cells [228] and they are also the most commonly used ones [229]. They are seen both as a therapeutic approach themselves, through their direct administration to patients—either genetically modified or not—and as a way to grow organoids in culture, for instance, which can also be administered to patients later [230]. These cells present potential for the treatment of different diseases, due to their immune modulation and differentiation properties, along with their tropism for injured tissues and their rich secretome, as it will be addressed in this review [229]. Hence, considering these characteristics of MSCs, alongside Klotho’s anti-inflammatory potential, we speculate that these cells can act like a “Trojan Horse’’ in vivo, delivering Klotho to the renal tissue, and that they could therefore modify and improve the microenvironment conditions for Klotho. This protein, in turn, would be able to ameliorate the surroundings conditions for MSCs as well, and consequently increase their efficacy in vivo. Therefore, we propose that MSCs and Klotho would act in a synergic way, contributing to the improvement of kidney conditions in CKD and AKI, as illustrated in Figure 5.
4.1. Mesenchymal Stem Cells
4.1.1. Properties and Characterization of Mesenchymal Stem Cells
4.1.2. Efficacy and Safety of Mesenchymal Stem Cells
4.2. Crosstalk between Klotho and Mesenchymal Stem Cells
4.3. Perspectives on MSC and Gene Therapy for Chronic and Acute Kidney Disease
4.3.1. MSC-Derived Extracellular Vesicles
4.3.2. MicroRNAs
4.3.3. MSCs Combined with Sodium-Glucose Co-Transporter-2 Inhibitors
4.3.4. Klotho, microRNAs and Genetically Modified MSCs in Chronic and Acute Kidney Disease
4.3.5. Challenges for the Clinical Application of MSCs
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Author/Year | Model Used | Study Design | Conclusion |
---|---|---|---|
Karalliedde, J., et al., 2013 [85] | Patients with diabetes type 2, presenting systolic hypertension and albuminuria | Single-Center, Double-Blind Randomized Controlled Trial | Inhibition of RAAS led to an increase in soluble Klotho levels. |
Saito, Y., et al., 2000 [86] | Rats with atherosclerosis | Preclinical Study | Klotho adenoviral delivery resulted in the mitigation of vascular endothelial dysfunction and reduction of blood pressure values |
Kuro-o, M., et al.,1997 [1] | Klotho-deficient mice | Preclinical Study | The animals presented artery calcification, cardiac fibrosis and hypertrophy. Klotho might participate in the signaling pathways involved in these processes. |
Xie, J., et al., 2015 [87] | Klotho-deficient mice | Preclinical Study | The increase in soluble Klotho levels attenuated cardiac remodeling in CKD animals. Decrease in this protein level is proposed to be an independent factor for cardiomyopathy in CKD. |
Ding, et al., 2019 [88] | Mice with angiotensin-II infusion | Preclinical Study | Klotho was related to the decrease of cardiac FGF-23 expression in vitro and in vivo; moreover, it prevented cardiac remodeling and dysfunction in this model. |
Memmos, et al., 2019 [84] | 79 patients on dialysis | Prospective Cohort Study | Low levels of Klotho are correlated with an increased risk of cardiovascular disease and reduced overall survival in these patients. It might contribute to cardiovascular disease in individuals with CKD. |
Brandenburg, V.M., et al., 2015 [89] | 2948 patients | Multicenter Longitudinal Study | In individuals with normal kidney function, Klotho does not act as a predictive marker of cardiovascular and mortality risk. |
Pan, H.C., et al., 2018 [90] | 168 patients with diabetes type 2 | Prospective Study | Low levels of Klotho are associated with cardiovascular outcomes, such as coronary disease. In these patients, Klotho level is a predictor for vascular events. |
Gutierrez, O.M., et al., 2009 [91] | 162 patients with CKD | Cross-Sectional Study | FGF-23 is correlated with vascular dysfunction, such as left ventricular mass index and hypertrophy in these individuals. |
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Franco, M.L.; Beyerstedt, S.; Rangel, É.B. Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics 2022, 14, 11. https://doi.org/10.3390/pharmaceutics14010011
Franco ML, Beyerstedt S, Rangel ÉB. Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease. Pharmaceutics. 2022; 14(1):11. https://doi.org/10.3390/pharmaceutics14010011
Chicago/Turabian StyleFranco, Marcella Liciani, Stephany Beyerstedt, and Érika Bevilaqua Rangel. 2022. "Klotho and Mesenchymal Stem Cells: A Review on Cell and Gene Therapy for Chronic Kidney Disease and Acute Kidney Disease" Pharmaceutics 14, no. 1: 11. https://doi.org/10.3390/pharmaceutics14010011