Treating Systemic Klotho Deficiency

Pastor, Johanne; Moe, Orson W.

doi:10.1159/000499864

Cited by 3 publications

(2 citation statements)

References 8 publications

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“…This observation was also demonstrated in HK-2 cells exposed to TGF-β1. Thus, strategies to upregulate Klotho expression or block Klotho downregulation may be applicable for attenuating RIF and delaying CKD progression [12,57]. However, the molecular mechanism underlying Klotho deficiency in kidney diseases is still not yet fully understood, leading to intensive ongoing research in this area.…”

Section: Discussionmentioning

confidence: 99%

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

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Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-β1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-β1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion:ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.

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Section: Discussionmentioning

confidence: 99%

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

View full text Add to dashboard Cite

show abstract

“…This implies a Klotho-driven upregulation of creatine carriers, presumably by stabilizing the carrier protein in the cell membrane, which likely nominates Klotho protein as a therapeutic proxy to accelerate creatine uptake through CT1. Several methods have been developed lately to raise Klotho levels ( 13 ), including a transgenic insertion of the klotho gene, a recombinant Klotho protein administration, or using angiotensin-converting enzyme inhibitor and thiazolidinediones. However, nutrition-related interventions might also be capable of enhancing endogenous Klotho production, and perhaps to unlocks CT1 for brain creatine uptake ( Figure 1 ).…”

Section: Ct1 Stimulation and Klotho Proteinmentioning

confidence: 99%