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GH–IGF1 axis in spermatogenesis and male fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Antonio Mancini, Carmine Bruno, Andrea Palladino, Edoardo Vergani, Elena Giacchi
Finally, the discovery of Klotho, a protein involved in antiaging effects in mice phenotypes, has thrown light on connections between peripheral organs and pituitary. In humans Klotho is mainly expressed in the kidney but also in the endothelium, where it induces nitric oxide (NO) production. Klotho is a regulator of GH secretion, as shown in both animals and humans, inhibiting negative IGF-1 feedback on GH release; its levels are low in GH-deficient subjects; however, the complex relationships with the GH axis are still to be clarified (35). A schematic representation of the GH–IGF-1 axis is reported in Figure 6.1.
A Synopsis on Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Another potential route of intervention is through the manipulation of the klotho gene. This gene codes for one membrane protein and one secreted transcript, which acts as a circulating hormone (da Costa et al. 2016). Mutations in the klotho gene have resulted in accelerated aging in mice (Kuro-o et al. 1997) and the overexpression of klotho has been accompanied by an extension in life span by about 30% (Kurosu et al. 2005). The action mechanism of this gene remains unclear (the insulin/IGF-1 signaling pathways may be involved [Tsujikawa et al. 2003]), though more research is needed to confirm the role of the klotho gene in the aging process, which also holds true for other genes, which have also been described as having a role in the aging process(es) (Hackl et al. 2010, ElSharawy et al. 2012, Klement et al. 2012, Zhong et al. 2015).
Epigenetics
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Christian Thomas, Sara C. Zapico
Regarding ncRNA, miRNAs affect gene expression during the aging process in mice and modulate senescence in human cell lines (Smith-Vikos and Slack 2012). For instance, miR-34a has been designated as an aging marker in several tissues and systems. Boon et al. (Boon et al. 2013) demonstrated that miR-34a is upregulated in the aging heart and its inhibition reduces cell death and fibrosis following acute myocardial infarction. miRNA-339 and miRNA-556 bind three untranslated regions of Klotho mRNA, an anti-aging protein whose expression decreases in normal aging of mice. Experimental results pointed out that these miRNAs can directly decrease this protein, playing a role in its regulation (Mehi et al. 2014). Apart from these intracellular miRNAs, several circulatory miRNAs seem to be common for the major age-related diseases since they have two opposite roles, activating and inhibiting inflammatory pathways (Olivieri et al. 2013).
Relationships between blood bone metabolic biomarkers and anemia in patients with chronic kidney disease
Published in Renal Failure, 2023
Fan Li, Xiaoxue Ye, Guang Yang, Hui Huang, Anning Bian, Changying Xing, Shaowen Tang, Jing Zhang, Yao Jiang, Huimin Chen, Caixia Yin, Lina Zhang, Jing Wang, Yaoyu Huang, Wenbin Zhou, Huiting Wan, Xiaoming Zha, Ming Zeng, Ningning Wang
Klotho deficiency is a characteristic feature of CKD; however, the role of α-klotho in renal anemia remains unclear. Our study demonstrated that blood α-klotho levels were positively associated with Hb levels in CKD patients. Treatment of anemia with EPO has been demonstrated to enhance renal and extrarenal production of α-klotho in CKD patients [35]. However, several studies provided contradictory results. Yang Xu et al. [36] suggested that there may be a negative feedback mechanism between EPO and α-klotho, such that increasing α-klotho suppresses the production of EPO in CKD; so, low expression of α-klotho may be a compensatory mechanism to attenuate the effects of anemia. Another study showed that the expression of HIF-1 α and HIF-2 α is significantly upregulated in α-klotho-/- bone tissues, resulting in local overexpression of EPO [51]. The relationship between α-klotho and renal anemia is also affected by iron metabolism and vitamin D, but more research is required to investigate this connection [36]. Although the specific mechanism of α-klotho in renal anemia remains unclear, it is certain that α-klotho can serve as a therapeutic target for renal anemia treatment.
Soluble klotho as an effective biomarker to characterize inflammatory states
Published in Annals of Medicine, 2022
Numerous studies that have investigated the functions of Klotho have demonstrated its distinctive role in vascular homeostasis. In CVD, Klotho suppresses IL-6 production in endothelial cells [43], inhibiting TRPC6 channels in cardiomyocytes [44], and inactivates ROS and NF-κB-mediated inflammation [45]. In the kidneys, Klotho reduces podocyte injuries through inhibition of insulin-like growth factor 1, protein kinase-1/2, and p38 mitogen-activated protein kinase [46]. It also increases fibroblast growth factor receptor levels and glycolytic capacity and decreases glomerular albumin permeability in hyperglycemia [39]. Accordingly, the role of s-Klotho as an inverse indicator of inflammation may be more prominent in cardiovascular and kidney-related diseases. Future studies are required to enhance our understanding of s-Klotho levels in different diseases.
Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway
Published in Renal Failure, 2022
Ziying Wang, Zhuanli Zhou, Yanan Zhang, Fuwen Zuo, Junyao Du, Mingwei Wang, Muchen Hu, Yu Sun, Xiaojie Wang, Min Liu, Yan Zhang, Wei Tang, Fan Yi
Moreover, we also found that DGKE regulated the expression of Klotho, which was initially identified as an antiaging protein and is also mainly expressed in the kidney [29]. Numerous studies have indicated that Klotho is significantly correlated with the development and progression of AKI and CKD. Exogenous supplementation or overexpression of endogenous Klotho prevents and ameliorates injury, promotes recovery, and suppresses fibrosis to mitigate the development of CKD [30,31]. Therefore, Klotho is considered as a potential diagnostic biomarker and therapeutic target for the prevention of kidney injury [32]. However, the endogenous regulation of Klotho expression, release, and metabolism remains largely unknown. Considering that KLF15 is an important transcription factor involved in AKI, and that both Klotho and KLF15 are regulated by DGKE in this study, we therefore examined the interaction between Klotho and KLF15. Our results showed that Klf15 gene silencing counteracted the effects of DGKE on Klotho expression. However, pretreatment with exogenous recombinant Klotho protein had no effects on KLF15 and DGKE expression, indicating that Klotho might be a downstream target of KLF15 directly or indirectly. Therefore, although our current data are very limited, we proposed that DGKE-induced Klotho expression is mediated, at least in part, by KLF15. Further studies are needed to detect whether Klotho expression is directly regulated by KLF15.