Improving Brain Creatine Uptake by Klotho Protein Stimulation: Can Diet Hit the Big Time?

Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and have antiinflammatory and antifibrotic properties. The course of diabetes mellitus and diabetic nephropathy resembles premature cellular senescence and causes the activation of various proinflammatory and profibrotic processes. Klotho was shown to exert many beneficial effects in these disorders. The expression of Klotho protein is downregulated in early stages of inflammation and diabetic nephropathy by proinflammatory factors. Therefore, its therapeutic effects are diminished in this disorder. Significantly lower urine levels of Klotho may serve as an early biomarker of renal involvement in diabetes mellitus. Recombinant Klotho administration and Klotho overexpression may have immunotherapeutic potential for the treatment of both diabetes and diabetic nephropathy. Therefore, the current manuscript aims to characterize immunopathologies occurring in diabetes and diabetic nephropathy, and tries to match them with antiinflammatory actions of Klotho. It also gives reasons for Klotho to be used in diagnostics and immunotherapy of these disorders.

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Sugar sweetened beverage consumption is positively associated with Klotho levels at two years of age in LatinX youth

BMC Nutrition ◽

10.1186/s40795-021-00423-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sofia Villagomez ◽

Dena B. Dubal ◽

Jessica Hawkins ◽

Dan Wang ◽

Janet M. Wojcicki

Keyword(s):

San Francisco ◽

Low Income ◽

Accelerated Aging ◽

Positive Association ◽

Dietary Factors ◽

Sugar Sweetened Beverage ◽

Protein Levels ◽

Sweetened Beverages ◽

Klotho Protein

Abstract Background Klotho is an anti-aging protein mainly expressed in the kidneys with a smaller amount expressed in adipose tissue. Klotho effects include roles in reducing oxidative stress, insulin signaling, adipogenesis and glucose metabolism. Few studies have investigated the role of dietary factors such as sugar sweetened beverages (SSBs) on serum α-klotho levels in young children. Methods Data was collected from 60 low-income Latina pregnant women and their infants in San Francisco from birth until 2 years of life and examined for associations between dietary factors and child secreted α-klotho protein levels at 2 years. Results Mean α-klotho levels were 1782.96 ± 874.56 pg/mL at 2 years of age. Any consumption of SSBs was independently associated with increased α-klotho levels (Beta = 682.79, 95%CI 67.50, 1298.09; p = 0.03). Household income ranging from $25,000 to $50,000 was also correlated to higher levels of α-klotho in children compared with lower income levels (<$25,000) (Beta = 1613.35, 95%CI 527.37, 2699.33; p = 0.005). Conclusions The positive association between SSB intake and α-klotho levels at 2 years may reflect higher phosphate levels consistent with SSB intake. Higher socioeconomic status may be a proxy for reduced stress exposure in children, also associated with higher α-klotho levels. Future studies should evaluate the early impact of exposures to SSBs, stress and accelerated aging in children.

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Establishment of the Anti-Klotho Monoclonal Antibodies and Detection of Klotho Protein in Kidneys

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1999.2009 ◽

2000 ◽

Vol 267 (2) ◽

pp. 597-602 ◽

Cited By ~ 111

Author(s):

Yukinari Kato ◽

Emi Arakawa ◽

Satoko Kinoshita ◽

Akio Shirai ◽

Akiko Furuya ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Klotho Protein

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Effect of α-Lipoic Acid Combined with Creatine Monohydrate on Human Skeletal Muscle Creatine and Phosphagen Concentration

International Journal of Sport Nutrition and Exercise Metabolism ◽

10.1123/ijsnem.13.3.294 ◽

2003 ◽

Vol 13 (3) ◽

pp. 294-302 ◽

Cited By ~ 25

Author(s):

Darren G. Burke ◽

Philip D. Chilibeck ◽

Gianni Parise ◽

Mark A. Tarnopolsky ◽

Darren G. Candow

Keyword(s):

Skeletal Muscle ◽

Lipoic Acid ◽

Human Skeletal Muscle ◽

Vastus Lateralis ◽

Creatine Supplementation ◽

Creatine Monohydrate ◽

Glucose Disposal ◽

Creatine Uptake ◽

Total Creatine ◽

Muscle Creatine

α-lipoic acid has been found to enhance glucose uptake into skeletal muscle in animal models. Studies have also found that the co-ingestion of carbohydrate along with creatine increases muscle creatine uptake by a process related to insulin-stimulated glucose disposal. The purpose of this study was to determine the effect of α-lipoic acid on human skeletal muscle creatine uptake by directly measuring intramuscular concentrations of creatine, phosphocreatine, and ad-enosine triphosphate when creatine monohydrate was co-ingested with α-lipoic acid. Muscle biopsies were acquired from the vastus lateralis m. of 16 male subjects (18–32 y) before and after the experimental intervention. After the initial biopsy, subjects ingested 20 g · d−1 of creatine monohydrate, 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose, or 20 g · d−1 of creatine monohydrate + 100 g · d−1 of sucrose + 1000 mg · d−1 of α-lipoic acid for 5 days. Subjects refrained from exercise and consumed the same balanced diet for 7 days. Body weight increased by 2.1% following the nutritional intervention, with no differences between the groups. There was a significant increase in total creatine concentration following creatine supplementation, with the group ingesting α-lipoic acid showing a significantly greater increase (p < .05) in phosphocreatine (87.6 → 106.2 mmol · kg−1 dry mass [dm]) and total creatine (137.8 → 156.8 mmol · kg−1 dm). These findings indicate that co-ingestion of α-lipoic acid with creatine and a small amount of sucrose can enhance muscle total creatine content as compared to the ingestion of creatine and sucrose or creatine alone.

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Involvement of the Klotho Protein in Dentin Formation and Mineralization

The Anatomical Record ◽

10.1002/ar.20630 ◽

2008 ◽

Vol 291 (2) ◽

pp. 183-190 ◽

Cited By ~ 9

Author(s):

Hironobu Suzuki ◽

Norio Amizuka ◽

Kimimitsu Oda ◽

Masaki Noda ◽

Hayato Ohshima ◽

...

Keyword(s):

Klotho Protein ◽

Dentin Formation

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Regulation of the Voltage Gated K+Channel Kv1.3by Recombinant Human Klotho Protein

Kidney & Blood Pressure Research ◽

10.1159/000368472 ◽

2014 ◽

Vol 39 (6) ◽

pp. 609-622 ◽

Cited By ~ 9

Author(s):

Ahmad Almilaji ◽

Sabina Honisch ◽

Guilai Liu ◽

Bernat Elvira ◽

Sumant Singh Ajay ◽

...

Keyword(s):

K Channel ◽

Voltage Gated ◽

Klotho Protein

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Abstract 319: Intermedin Attenuates Vascular Calcification by Upregulating Klotho via CRLR/RAMP3 Receptor Complex and cAMP/PKA Signaling Pathway in Rats With Chronic Kidney Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.319 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Jin-Rui Chang ◽

Yue-Long Hou ◽

Wei-Wei Lu ◽

Jin-Sheng Zhang ◽

Yan-Rong Yu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Smooth Muscle ◽

Kidney Disease ◽

Signaling Pathway ◽

Vascular Calcification ◽

Small Interfering Rna ◽

Calcium Deposition ◽

Alp Activity ◽

Klotho Protein ◽

Interfering Rna

Vascular calcification (VC) is highly associated with increased morbidity and mortality in patients with advanced chronic kidney disease(CKD). We previously reported that paracrine/autocrine factor intermedin (IMD) could protect against VC. In the present study we assessed the hypothesis that IMD inhibits VC by upregulating klotho protein. VC in CKD rat was induced by 5/6 nephrectomy plus vitamin D 3 administration and vascular smooth muscle cells (VSMCs) calcification was induced by calcifying media containing β -glycerophosphate and CaCl 2 . IMD (100 ng kg -1 h -1 ) was systemically administered by a mini-osmotic pump. CKD rat aortas showed lower IMD content and increased expression of its receptors (calcitonin receptor-like receptor,CRLR/receptor activity-modifying protein 3, RAMP3), along with increased aortic alkaline phosphatase (ALP) activity and calcium deposition. In vivo administration of IMD significantly reduced aortic ALP activity and calcium deposition in CKD rats when compared with vehicle treatment, which was further confirmed in cultured VSMCs. Concurrently, the loss of smooth muscle lineage markers and klotho protein in aortas was rescued by administering IMD to CKD rats with VC. However, the inhibitory effects of IMD on VC were abolished upon pre-treatment with small interfering RNA to reduce klotho. Moreover, the increased effects of IMD on klotho were abolished upon pretreatment with small interfering RNA to reduce its receptors or with PKA inhibitor H89. These results demonstrated that IMD attenuates VC by upregulating klotho via CRLR/RAMP3-cAMP/PKA signaling pathway in rat with CKD. IMD is an important paracrine/autocrine protective factor for VC.

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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

Journal of Diabetes Research ◽

10.1155/2018/7163652 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Inbal Dahan ◽

Nadia Thawho ◽

Evgeny Farber ◽

Nakhoul Nakhoul ◽

Rabea Asleh ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Immunohistochemical Analysis ◽

Major Determinant ◽

Major Player ◽

New Ideas ◽

Klotho Protein ◽

Iron Deposits ◽

Renal Tubular ◽

And Oxidative Stress ◽

Renal Expression

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 theα-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 theα-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 decreasedα-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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