Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus

Nie, Fang; Wu, Dongming; Du, Hongfei; Yang, Xianggui; Yang, Min; Pang, Xueli; Yang, Xu

doi:10.1016/j.jdiacomp.2016.11.008

Cited by 64 publications

(68 citation statements)

References 29 publications

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“…We further found out that in the Hp 2-2 genotype, α -klotho renal expression is gradually reduced with the progression in CKD stages, and this decrease is more prominent in the diabetic state. This association is in agreement with previous studies that have shown that renal α-klotho gene expression is regulated by pathophysiological conditions including hypertension, diabetes, and chronic renal failure in animal models and in humans [ 16 , 17 , 20 , 29 – 32 ].…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have indicated that renal α-klotho gene expression is regulated by pathophysiological conditions including long-term hypertension, oxidative stress, diabetes, and chronic renal failure in both animal models and humans [ 16 , 17 , 20 , 29 – 32 ]. Hence, we evaluated whether the increased renal iron deposits associated with the Hp 2-2 genotype also affect the α -klotho renal expression both in DN mice and patients.…”

Section: Resultsmentioning

confidence: 99%

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The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

Dahan

Thawho

Farber

et al. 2018

Journal of Diabetes Research

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The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the α-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased α-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

Dahan

Thawho

Farber

et al. 2018

Journal of Diabetes Research

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“…Klotho regulation by proteinuria was further confirmed in other models of proteinuria and was shown to be independent of inflammatory cytokines . In humans, albuminuria has been associated with decreased soluble Klotho, alterations of FGF‐23 and increased serum phosphate . Another study confirmed the association of albuminuria to decreased FGF‐23 biological activity and a worse prognosis in a CKD cohort .…”

Section: Introductionmentioning

confidence: 68%

“…23 In humans, albuminuria has been associated with decreased soluble Klotho, alterations of FGF-23 and increased serum phosphate. 22,[24][25][26][27] Another study confirmed the association of albuminuria to decreased FGF-23 biological activity and a worse prognosis in a CKD cohort. 28 Interestingly, in the Chronic Renal Insufficiency Cohort (CRIC) study, the association of proteinuria with mortality was noticeably lessened by the integration of FGF-23 levels.…”

Section: Introductionmentioning

confidence: 81%

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

et al. 2019

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Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD‐ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half‐life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3−/− Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4‐PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria‐induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.

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“…Diabetes mellitus as a chronic disease causes some complications, including nephropathy. It is also suggested that plasma Klotho concentration, or more precisely the disappearance of a compensatory increase in serum concentration, may be an early marker for predicting deterioration of renal function among patients with type 2 diabetes [50,51]. We also know that serum Klotho may have a protective effect against atherosclerosis and endothelial dysfunction in type 1 DM [52].…”

Section: Is There a Relationship Between Klotho Protein And Type 1 DImentioning

confidence: 99%

Klotho protein function among patients with type 1 diabetes

Flotyńska

Uruska

Araszkiewicz

et al. 2018

Endokrynologia Polska

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The fibroblast growth factor 23 (FGF23) and Klotho system play a very important role in the regulation of the human body metabolism. On the one hand, they promote longevity, and on the other hand they promote insulin resistance. Nowadays, accelerated aging in diabetes as the main consequence of chronic complications of the disease is postulated. Signalling pathways induced by insulin, insulin-like growth factor (IGF-1), and their homologues play an important role in controlling the aging process. Because FGF23/Klotho system affects glucose metabolism and gene expression of antioxidant enzymes, changes in its concentration may be a marker of chronic complications of diabetes or a treatment option. Despite huge improvements in the treatment of diabetes, its chronic complications remain an important clinical problem. An interesting issue is the relationship between the concentration of FGF23/Klotho and management of the disease, duration, insulin resistance, and development of complications in type 1 diabetes. (Endokrynol Pol 2018; 69 (6): 696-704)

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Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus

Cited by 64 publications

References 29 publications

The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and Mice

Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Klotho protein function among patients with type 1 diabetes

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