Soluble α-Klotho as a Novel Biomarker in the Early Stage of Nephropathy in Patients with Type 2 Diabetes

Lee, Eun Young; Kim, Sang Soo; Lee, Ji Sung; Kim, In Joo; Song, Sang Heon; Kuy, Seung; Park, Kyu Sang; Kang, Jin Ku; Chung, Choon Hee

doi:10.1371/journal.pone.0102984

Cited by 71 publications

(75 citation statements)

References 24 publications

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“…It is likely that Klotho may exert a multitude of actions to mitigate the activation of intrarenal RAS as well as systemic aldosterone production. Overall, strong evidence demonstrates the suppression of renal Klotho expression in diabetic renal disease, and more vigorous functional studies are needed to define the renoprotective action of this antiaging protein as well as its relationship with intrarenal RAS [30][31][32][33][34][35].…”

Section: Klotho-vitamin D-vdr Axismentioning

confidence: 99%

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Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in patients with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and continue to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic alterations interact synergistically, and have been reported to activate local RAAS resulting in increased angiotensin-2. In spite the early and chronic treatment with converting enzyme inhibitors and angiotensin receptor blocking drugs, the number of patients reaching end stage renal disease and replacement therapy are increasing.Recently different pathways were proposed to be involved in the pathogenesis of diabetic nephropathy, including the autophagy process, Klotho and the selective agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the protective autophagic process and increase in cellular damage.α-Klotho is a multifunctional protein highly expressed in the kidney. The klotho protein has endogenous anti fibrotic function via antagonism of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho in early stage of diabetic nephropathy may contribute to the progression of DN by accelerated fibrogenesis.The selective vitamin D agonist and his receptor, play a protective pathway in diabetic nephropathy. A key renoprotective function of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This antiproteinuric effect and the deceleration of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the different new mechanisms involved in diabetic nephropathy and future therapeutic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the selective active vitamin D.

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Section: Klotho-vitamin D-vdr Axismentioning

confidence: 99%

“…In addition to the effect of Klotho on Transforming Growth Factor β (TGF-β), suppressive effects of Klotho on the insulin-like growth factor pathway may be associated with inhibitory action on renal fibrosis [33][34][35] and cardio-renal protection in high oxidative stress conditions such as diabetes and its complications.…”

Section: Klotho-vitamin D-vdr Axismentioning

confidence: 99%

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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“…There were statistically significant correlations between categories of progressively worsening albuminuria and lower plasma a-klotho levels [25]. Currently, preventing deceases in aklotho can be a potential therapeutic strategy for early diabetic nephropathy.…”

Section: Wntmentioning

confidence: 86%

Research Advances on the Genetic Mechanism of Diabetic Nephropathy

Ti¹,

Li²,

Qiao³

et al. 2017

J Clin Exp Nephrol

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Aim: This article focuses on the genetic mechanisms, with an aim to provide certain theoretical and experimental foundation for the future diagnosis and treatment of diabetic nephropathy. Five common genes were selected in this article including ACE, Klotho, MicroRNA, CERS and VDR. Methods:To learn about the newest study trends on this topic through searching numerous international and domestic databases (such as CNKI, CBMdisc, PUBMED, EBMase) aiming to obtain meaningful conclusions in order to write a valuable summarization.Results: These five genes both play important roles in the pathogenesis of diabetic nephropathy: ① The I allele of ACE gene is the protective gene that prevents type 2 diabetes mellitus patients from developing diabetic Nephropathy; ② In diabetic nephropathy, the level of Klotho mRNA and Klotho protein is decreased by the RAAS, TGFβ, PPAγ, and Wnt signaling pathways; ③ miR-29c, which is involved in the regulation of the Spry1/Rho signaling pathway, can be used as a new target for the treatment of diabetic nephropathy; The SNP (rs267734) in the CERS2 gene is associated with an increase in albuminuria among patients with diabetes; The occurrence of diabetic nephropathy is associated with vitamin D receptor gene genetic polymorphisms. Conclusion:With an ever-increasing access to this subject, we can further our understanding of the pathogenesis of DN and broaden the research field until accomplishing the target of prevention of DN through the creation of new target drug and accurate prediction of disease. Further study about the genetic mechanism of DN especially T1DN remains a vital task.

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“…However, plasma sKlotho decreased in proportion to increasing urinary albumin excretion, suggesting a possible initial adaptive increase to preserve kidney function. 45 In animal models of CKD, reduced levels of renal, plasma, and urinary Klotho have been detected. Overexpression or supplementation with sKlotho have resulted in improved renal function and ameliorated renal histologic changes, thus suggesting that sKlotho may be renoprotective by reducing oxidative stress, cell senescence, and apoptosis.…”

Section: Vegf-a 165 Bmentioning

confidence: 99%

Alternative Splicing in CKD

Stevens

Oltean

2016

JASN

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Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with $94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.

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Soluble α-Klotho as a Novel Biomarker in the Early Stage of Nephropathy in Patients with Type 2 Diabetes

Cited by 71 publications

References 24 publications

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Research Advances on the Genetic Mechanism of Diabetic Nephropathy

Alternative Splicing in CKD

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