Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Typiak, Marlena; Kulesza, Tomasz; Rachubik, Patrycja; Rogacka, Dorota; Audzeyenka, Irena; Angielski, S; Saleem, Moin A.; Piwkowska, Agnieszka

doi:10.3390/ijms22157867

Cited by 18 publications

(16 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite the general negative relationship between s-Klotho levels and inflammatory biomarkers, under certain circumstances, the association may be positive. A recent study measuring serum and urine s-Klotho levels in rats found significantly higher serum levels of s-Klotho in diabetic subjects [ 39 ]. Initially, this appeared to conflict with our findings, but closer inspection revealed a possible mechanism explained by the increased Klotho-shedding enzymes, a disintegrin and metalloprotease (ADAM)10 and ADAM17, in diabetic models.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Soluble klotho as an effective biomarker to characterize inflammatory states

Chen

2022

Annals of Medicine

View full text Add to dashboard Cite

Background & Aims Soluble α-Klotho (s-Klotho) is a circulating protein with pleiotropic effects that mainly induce protective effects. Our study investigates the associations between s-Klotho and several established inflammatory biomarkers, with the aim of examining whether s-Klotho levels are representative of inflammatory states. Methods A total of 11,128 eligible participants from NHANES 2007–2016 were included in our study. Levels of four inflammatory biomarkers, uric acid (UA), C-reactive protein (CRP), white blood cell (WBC) count, and mean platelet volume (MPV), were examined for their relationship with s-Klotho levels. Sub-analyses sorted the total population by gender and into four quartiles. Linear regression models were used to evaluate the strengths of associations. Results All four inflammatory biomarkers were significantly associated with s-Klotho levels. UA, CRP, and WBC count showed an inverse association, while MPV showed a direct one. Of the four markers, UA was most strongly correlated with s-Klotho levels (β coefficient: −28.89 in unadjusted model, p <.001), and this relationship was stronger in women than in men (β coefficient of UA in men: −22.01, p <.001; in women: −31.54, p <.001). In addition, all four biomarkers manifested stronger associations with s-Klotho in higher quartiles, and the highest absolute values of β coefficients appeared in Q4 vs. Q1. Conclusion s-Klotho is significantly associated with well-recognized inflammatory biomarkers. A decrease in s-Klotho levels implies a general inflammatory status; therefore, s-Klotho serves as a potential biomarker that is inversely correlated with inflammatory conditions. Further applications in clinical practice will provide us with a better understanding of its role. Key messages Soluble α-Klotho (s-Klotho) levels are significantly associated with the inflammatory markers uric acid, C-reactive protein, white blood cell count, and mean platelet volume. S-Klotho is involved in inflammatory processes and plays a protective role. S-Klotho may serve as an inverse indicator of inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Soluble klotho as an effective biomarker to characterize inflammatory states

Chen

2022

Annals of Medicine

View full text Add to dashboard Cite

show abstract

“…On the one hand, sKlotho is cleaved from cell membrane mKlotho by metalloproteinases (ADAM) including ADAM 10 and ADAM17; thereafter, its concentration is influenced by ADAMs. This may be one cause of the increased sKlotho level, while the mKlotho level is decreased in the DKD model (Typiak et al, 2021;Ciardullo and Perseghin, 2022). On the other hand, sKlotho is also generated by alternative mRNA splicing and the existing ELISA assays were unable to distinguish whether sKlotho results from shedding of the extracellular domain of mKlotho or alternative splicing of its transcript.…”

Section: Causes Of Controversy Of Sklotho As a Clinical Marker In Ckd...mentioning

confidence: 99%

The controversy of klotho as a potential biomarker in chronic kidney disease

Liu

Sha

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Klotho is an identified longevity gene with beneficial pleiotropic effects on the kidney. Evidence shows that a decline in serum Klotho level occurs in early chronic kidney disease (CKD) and continues as CKD progresses. Klotho deficiency is associated with poor clinical outcomes and CKD mineral bone disorders (CKD-MBD). Klotho has been postulated as a candidate biomarker in the evaluation of CKD. However, the evidence for the clinical significance of the relationship between Klotho and kidney function, CKD stage, adverse kidney and/or non-kidney outcomes, and CKD-MBD remains inconsistent and in some areas, contradictory. Therefore, there is uncertainty as to whether Klotho is a potential biomarker in CKD; a general consensus regarding the clinical significance of Klotho in CKD has not been reached, and there is limited evidence synthesis in this area. To address this, we have systematically assessed the areas of controversy, focusing on the inconsistencies in the evidence base. We used a PICOM strategy to search for relevant studies and the Newcastle–Ottawa Scale scoring to evaluate included publications. We reviewed the inconsistent clinical findings based on the relationship of Klotho with CKD stage, kidney and/or non-kidney adverse outcomes, and CKD-MBD in human studies. Subsequently, we assessed the underlying sources of the controversies and highlighted future directions to resolve these inconsistencies and clarify whether Klotho has a role as a biomarker in clinical practice in CKD.

show abstract

“…The consequent induction of inflammation, fibrosis, hemodynamic alterations, oxidative stress, and apoptosis are the main pathogenic characteristics of DN ( Barrera-Chimal and Jaisser, 2020 ; Kushwaha et al, 2020 ; Opazo-Ríos et al, 2020 ; Thongnak et al, 2020 ), but there is emerging evidence that additional signaling molecules function in the pathogenesis of DN. These include renal endothelial-related molecules (endothelial sirtuin 3 [SIRT3] ( Wang et al, 2019c ), endothelial glucocorticoid receptors [E-GRs] ( Srivastava et al, 2021a ), and endothelial fibroblast growth factor receptor 1 [FGFR1]) ( Typiak et al, 2021 ), and the podocyte-glucocorticoid receptor (P-GR) ( Srivastava et al, 2021b ). E-GR and P-GR have anti-fibrotic effects, and their loss or knock-out-promotes fibrosis and accelerates DN ( Srivastava et al, 2021a ; Srivastava et al, 2021b ).…”

Section: Gsdms and Gsdmementioning

confidence: 99%

“…However, FGFR1, together with an appropriate rate of glycolysis in podocytes, is essential for maintenance of the normal filtration barrier ( Typiak et al, 2021 ). The endothelial protein SIRT3 regulates the redox balance and this decreases hyperglycemia-induced vascular inflammation, increases cell survival, and restores AMPK-mediated mitochondrial homeostasis ( Wang et al, 2019c ).…”

Section: Gsdms and Gsdmementioning

confidence: 99%

Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy

Sun

Zhou

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Pyroptosis is a recently identified type of lytic programmed cell death, in which pores form in the plasma membrane, and cells swell, rupture, and then release their contents, including inflammatory cytokines. Molecular studies indicated that pyroptosis may occur via a gasdermin D (GSDMD) and caspase-1 (Casp1) -dependent classical pathway, a GSDMD and Casp11/4/5-dependent non-classical pathway, or a gasdermin E (GSDME) and Casp3-dependent pathway. Studies of animal models and humans indicated that pyroptosis can exacerbate several complications of diabetes, including diabetic nephropathy (DN), a serious microvascular complication of diabetes. Many studies investigated the mechanism mediating the renoprotective effect of GSDMD regulation in the kidneys of patients and animal models with diabetes. As a newly discovered regulatory mechanism, GSDME and Casp3-dependent pyroptotic pathway in the progression of DN has also attracted people’s attention. Z-DEVD-FMK, an inhibitor of Casp3, ameliorates albuminuria, improves renal function, and reduces tubulointerstitial fibrosis in diabetic mice, and these effects are associated with the inhibition of GSDME. Studies of HK-2 cells indicated that the molecular and histological features of secondary necrosis were present following glucose stimulation due to GSDME cleavage, such as cell swelling, and release of cellular contents. Therefore, therapies targeting Casp3/GSDME-dependent pyroptosis have potential for treatment of DN. A novel nephroprotective strategy that employs GSDME-derived peptides which are directed against Casp3-induced cell death may be a key breakthrough. This mini-review describes the discovery and history of research in this pyroptosis pathway and reviews the function of proteins in the gasdermin family, with a focus on the role of GSDME-mediated pyroptosis in DN. Many studies have investigated the impact of GSDME-mediated pyroptosis in kidney diseases, and these studies used multiple interventions, in vitro models, and in vivo models. We expect that further research on the function of GDSME in DN may provide valuable insights that may help to improve treatments for this disease.

show abstract

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration

Cited by 18 publications

References 52 publications

Soluble klotho as an effective biomarker to characterize inflammatory states

Soluble klotho as an effective biomarker to characterize inflammatory states

The controversy of klotho as a potential biomarker in chronic kidney disease

Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy

Contact Info

Product

Resources

About