A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling

Yuan, Qian; Ren, Qian; Li, Li; Tan, Huishi; Lu, Meizhi; Tian, Yuan; Huang, Lu; Zhao, Boxin; Fu, Haiyan; Hou, Fan Fan; Zhou, Lili; Liu, Youhua

doi:10.1038/s41467-022-28096-z

Cited by 61 publications

(69 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Many studies have documented that kidney injury is aggravated in the absence of Klotho, while the injury is ameliorated in the presence of Klotho, which corroborates that Klotho is a novel kidney-protective protein (Jin et al, 2016;Li et al, 2018;Takenaka et al, 2020;Yuan et al, 2022). Unsurprisingly, if Klotho expression is decreased or suppressed, its kidney-beneficial effects are abrogated.…”

Section: Discussionmentioning

confidence: 79%

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

View full text Add to dashboard Cite

BackgroundEnhanced inflammation and reduced Klotho are common features in chronic kidney disease (CKD). Inflammation induces DNA hypermethylation. This study assessed the performance of inflammatory marker C-C motif chemokine 5 (CCL5) in epigenetic regulation of Klotho expression.MethodsFifty CKD patients and 25 matched controls were enrolled, and serum CCL5 level, sKlotho level, and DNA methylation were evaluated in these subjects. A renal interstitial fibrosis (RIF) model with CKD was induced in mice via unilateral ureteral obstruction (UUO) in vivo and human proximal tubular epithelial (HK-2) cells treated with CCL5 in vitro. 5-aza-2′-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor was given to UUO mice. Hematoxylin and eosin (HE) and Masson trichrome staining were adopted to evaluate renal pathological changes. Methylation-specific PCR was performed to assess DNA methylation of Klotho promoter in the peripheral blood leucocytes (PBLs) from CKD patients and obstructive kidney from UUO mice. CCL5, Klotho, and DNA methyltransferases (DNMTs) were determined by ELISAs, immunofluorescence, or western blotting. HK-2 cells were exposed to CCL5 with or without 5-Aza and stattic, a p-signal transducer and activator of transcription 3 (STAT3) inhibitor, and expressions of p-STAT3, DNMT1, and Klotho were determined by western blotting.ResultsCCL5 upregulation concomitant with Klotho downregulation in serum and global DNA methylation in PBLs were observed in CKD samples. UUO contributed to severe renal interstitial fibrosis and enhanced expressions of fibrotic markers. Moreover, UUO increased the CCL5 level, induced Klotho promoter methylation, suppressed Klotho level, activated p-STAT3 signaling, and upregulated DNMT1 level. A similar observation was made in HK-2 cells treated with CCL5. More importantly, 5-Aza inhibited UUO-induced Klotho hypermethylation, reversed Klotho, downregulated p-STAT3 expressions, and ameliorated RIF in vivo. The consistent findings in vitro were also obtained in HK-2 cells exposed to 5-Aza and stattic.ConclusionThe CCL5/p-STAT3/DNMT1 axis is implicated in epigenetic regulation of Klotho expression in CKD. This study provides novel therapeutic possibilities for reversal of Klotho suppression by CKD.

show abstract

Section: Discussionmentioning

confidence: 79%

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

View full text Add to dashboard Cite

show abstract

“…Administration of s-Klotho protein inhibits TGF-β signaling and protects against renal fibrosis ( Doi et al, 2011 ). In a more specific way, a Klotho-derived peptide (30 amino acids) that inhibits TGF-β by binding to its receptor also protected against renal fibrosis ( Yuan et al, 2022 ). These experiments provide evidence that Klotho can suppress TGF-β activities in vivo .…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

“…GABA receptor agonist: Liu W, et al, 2021 ; Prud’homme et al, 2017a ; Son et al, 2019 ; Wang Q, et al, 2019 . Recombinant Klotho protein or peptides: Ali et al, 2020 ; Chen TH, et al, 2013 ; Doi et al, 2011 ; Gupta et al, 2022 ; Hu et al, 2017 ; Leon et al, 2017 ; Maltese et al, 2017 ; Mencke et al, 2017 ; Myung et al, 2022 ; Oh et al, 2018 ; Prud’homme et al, 2020 ; Rao Z, et al, 2019 ; Takenaka et al, 2018 , 2019 , 2020 ; Yang et al, 2015 ; Yuan et al, 2022 ; Zhong et al, 2020 . Gene therapy: Arbel Rubinstein et al, 2021 ; Franco et al, 2021 ; Lin & Sun, 2015a , b ; Ni et al, 2021 ; Mencke et al, 2017 ; Shin et al, 2019 ; Xiang et al, 2021 ; Zeng et al, 2019 .…”

Section: Approaches To Klotho-based Therapyunclassified

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

View full text Add to dashboard Cite

The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

show abstract

“…Previous studies have shown that α-KL is not only involved in the regulation of calcium and phosphorus metabolism and the inhibition of renal fibrosis in CKD (7,8), but as an in-vivo hormone, it also exerts anti-oxidative stress, anti-inflammatory, anti-apoptotic, and autophagy-regulating effects (9)(10)(11)(12). Under normal renal physiological conditions, α-KL, fibroblast growth factor receptor-1 (FGFR1) and fibroblast growth factor-23 (FGF23) bind to form a trimeric complex, which drives FGF23 phosphorylation and thus reduces serum Pi by inhibiting 1,25-dihydroxyvitamin D and parathyroid hormone synthesis, intestinal Pi absorption, and Pi reabsorption (13,14).…”

Section: Introductionmentioning

confidence: 99%

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Huang¹,

Li²,

Tan³

et al. 2022

Transl Androl Urol

View full text Add to dashboard Cite

Background: Alpha-klotho (α-KL) is not only related to the regulation of calcium-phosphorus metabolism, and fibrosis in chronic kidney disease (CKD), it is also involved in the regulation of many cognitive disorders.We conducted this study to investigate the effects of CKD on cognitive dysfunction and α-KL.Methods: Doxorubicin was used to induce a CKD model, which was validated by weight, 24-hour urine protein quantification, serum creatinine (Cr), blood urea nitrogen (BUN), and kidney hematoxylin-eosin (HE) staining. The Morris water maze (MWM) paradigm was used to assess the effects of CKD on cognitive behavior. The expression of α-KL in the hippocampus was detected using real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry (IHC).Results: (I) In the CKD group, the weight of the rats increased slowly (P<0.001), 24-hour urine protein increased (P<0.05), and Cr (P=0.026) and BUN levels (P=0.003) increased; (II) HE staining showed that in the CKD group there were changes in the structure, fibrosis, and inflammatory infiltration of the renal tissues, and changes in the structure, cell necrosis, and neuronal degeneration of the hippocampus; (III) in the MWM experiment, the escape latency of the CKD group was prolonged compared to that of the control group (P=0.043, 0.023), and the number of crossing the platform was reduced (P=0.003); (IV) in the CKD group, the expressions of α-KL messenger ribonucleic acid (P=0.0005) and α-KL protein (P=0.0005) in the hippocampus were downregulated. The IHC results showed that the expression of α-KL protein in the hippocampal region III cornus ammonis (CA3) of the CKD group region was also downregulated, and the α-KL-positive cells (P=0.019) and mean optical density (P=0.015) were decreased. Conclusions:The expression of α-KL appears to effect the cognitive function of CKD rats; thus, it may be a valuable target in the treatment of CKD with cognitive impairment.

show abstract

A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling

Cited by 61 publications

References 53 publications

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Effects of chronic kidney disease on cognitive function and α-klotho expression in hippocampus

Contact Info

Product

Resources

About