Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria

Maltese, Giuseppe; Fountoulakis, Nikolaos; Siow, RC; Gnudi, Luigi; Karalliedde, Janaka

doi:10.1007/s00125-017-4219-1

Cited by 28 publications

(30 citation statements)

References 13 publications

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“…In adults and children, serum Klotho levels have been associated with eGFR, 54,55 but have also been shown to be dependent on the level of proteinuria. 24,25 We then provide evidence that Klotho loss is specific to albumin, since it was not observed in analbuminemic collagen 4α3 knockout mice, a model of Alport syndrome characterized by proteinuria, increased FGF-23 plasma levels and decreased Klotho expression. 56,57 Whether the rescue of Klotho loss is related to fewer kidney lesions rather than the absence of albumin can be debated since the samples originated from a previous study where the analbuminemic Alport mice had less renal tubular injury, although renal function was still altered at late stages.…”

Section: Discussionmentioning

confidence: 90%

“…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%

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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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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 81%

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

et al. 2019

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“…Cheng L. et al have demonstrated that PPARγ regulates vascular smooth muscle cell calcification through the activation of Klotho [ 233 ]. While, another research team has demonstrated that the downregulation of Klotho is also involved in the modulation of microalbuminuria in subjects with type 1 diabetes [ 234 ]. Recently, it has been reported that Klotho proteins are expressed in human cardiomyocytes and in the sinoatrial node region, its level are down-regulated in higher cardiovascular risk patients [ 235 ] and in the alteration of sinoatrial node to function under stress [ 236 ].…”

Section: Genetic Impact On Agingmentioning

confidence: 99%

The Impact of Aging on Cardio and Cerebrovascular Diseases

Izzo

Carrizzo

Alfano

et al. 2018

IJMS

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A growing number of evidences report that aging represents the major risk factor for the development of cardio and cerebrovascular diseases. Understanding Aging from a genetic, biochemical and physiological point of view could be helpful to design a better medical approach and to elaborate the best therapeutic strategy to adopt, without neglecting all the risk factors associated with advanced age. Of course, the better way should always be understanding risk-to-benefit ratio, maintenance of independence and reduction of symptoms. Although improvements in treatment of cardiovascular diseases in the elderly population have increased the survival rate, several studies are needed to understand the best management option to improve therapeutic outcomes. The aim of this review is to give a 360° panorama on what goes on in the fragile ecosystem of elderly, why it happens and what we can do, right now, with the tools at our disposal to slow down aging, until new discoveries on aging, cardio and cerebrovascular diseases are at hand.

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“…Klotho has several effects in mice that resemble GABA therapy, such as improved β‐cell survival and insulin secretion . In humans, circulating concentrations of Klotho are decreased in individuals with either T1D or type 2 diabetes . We recently reported that GABA treatment markedly increases Klotho production by human β‐cells .…”

Section: Discussionmentioning

confidence: 99%

Combined effect of GABA and glucagon‐like peptide‐1 receptor agonist on cytokine‐induced apoptosis in pancreatic β‐cell line and isolated human islets

Son

Liu

et al. 2019

Journal of Diabetes

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Background Treatment with GABA or glucagon‐like peptide‐1 (GLP‐1) can preserve pancreatic β‐cell mass and prevent diabetes. Recently, we reported that the combination of GABA and sitagliptin (a dipeptidyl peptidase‐4 inhibitor that increases endogenous GLP‐1) was more effective than either agent alone in reducing drug‐induced β‐cell damage and promoting β‐cell regeneration in mice. However, in human islets, it remains unclear whether GABA and GLP‐1 exert similar effects. Methods To investigate GABA and GLP‐1 interactions, human islets or INS‐1 cells were treated with GABA and/or exendin‐4, a GLP‐1 receptor agonist (GLP‐1RA) in clinical use, and incubated with a cytokine mixture for 24 hours. Cleaved caspase‐3 and annexin V binding were measured by western blot and flow cytometry analysis, respectively, to investigate effects on cytokine‐induced apoptosis. Results Cytokine‐induced apoptosis was reduced by either GABA or exendin‐4 alone. This was markedly improved by combining GABA and exendin‐4, resulting in a reversal of apoptosis. The combination notably increased Akt pathway signaling. Furthermore, sirtuin‐1 (SIRT1) and α‐Klotho, both reported to have protective effects on β‐cells, were increased. Importantly, the combination ameliorated insulin secretion by human β‐cells. Conclusions The combination of GABA and a GLP‐1RA exerted additive effects on β‐cell survival and function, suggesting that this combination may be superior to either drug alone in the treatment of diabetes.

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Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria

Cited by 28 publications

References 13 publications

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

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

The Impact of Aging on Cardio and Cerebrovascular Diseases

Combined effect of GABA and glucagon‐like peptide‐1 receptor agonist on cytokine‐induced apoptosis in pancreatic β‐cell line and isolated human islets

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