Klotho Depletion Contributes to Increased Inflammation in Kidney of the <i>db/db</i> Mouse Model of Diabetes via RelA (Serine)536 Phosphorylation

Zhao, Yanhua; Banerjee, Sneha; Dey, Nilay; LeJeune, Wanda; Sarkar, Partha S.; Brobey, Reynolds; Rosenblatt, Kevin P.; Tilton, Ronald G.; Choudhary, Sanjeev

doi:10.2337/db10-1262

Cited by 210 publications

(193 citation statements)

References 48 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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“…Regarding insulin resistance, decreased activity of FGF21 due to downregulation of the FGF21 receptor cofactor b-Klotho may be involved (39). Methylglyoxal-driven protein glycation decreased expression of b-Klotho (40). By inducing Glo1 expression and decreasing methylglyoxal protein glycation, therefore, we likely corrected the functional deficit of b-Klotho and reengaged FGF21.…”

mentioning

confidence: 99%

“…This explains the resetting of insulin sensitivity to normal levels with the response greater for higher-BMI subject groups. Characteristics of increased b-Klotho was its blocking of inflammatory signaling to downregulate proinflammatory mediators IL8, MCP1, ICAM-1, and RAGE (40) and, via decreasing MCP-1, also suppressing of PTGS2 (41) (Fig. 5).…”

mentioning

confidence: 99%

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

et al. 2016

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Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m 2 ), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (237%, P < 0.05) and total body methylglyoxal-protein glycation (214%, P < 0.01). It decreased fasting and postprandial plasma glucose (25%, P < 0.01, and 28%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL $ min 21 $ m 22, P < 0.02), and improved arterial dilatation Dbrachial artery flowmediated dilatation/Ddilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (210%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

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“…16 This Klotho/Wnt interaction results in functional sequestration of Wnt ligands, and blocks Wnt-mediated b-catenin activation and its target gene expression. Therefore, loss of Klotho, which is common in aged kidneys and CKD, 13,17 will inevitably lead to Wnt/b-catenin activation and development of kidney lesions and renal insufficiency.…”

mentioning

confidence: 99%

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Zhou

Miao

et al. 2015

The American Journal of Pathology

133

117

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Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited b-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem, because it affects about 10% to 13% of the adult population worldwide.1e3 Among many risk factors for developing CKD, aging is an independent and strong predictor for progressive renal insufficiency. 4 The elderly population also tends to develop hypertension and cardiovascular disease, characteristic features consistent with the activation of the renin-angiotensin system (RAS). 5,6 These observations suggest that aging, CKD, and RAS activation might be intimately linked. However, the molecular details behind these connections are not fully understood.RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II type I and type II receptors (AT1 and AT2, respectively).7e9 Two main enzymes in this system, renin and ACE, lead to the formation of angiotensin II, the principal active peptide of RAS, which mediates both blood pressureedependent and eindependent kidney damage in CKD. Several factors can induce RAS activation, such as reactive oxygen species, hyperglycemia, and albumin. 10,11 We recently found that all RAS genes contain T cell factor/ lymphoid enhancer-binding factor binding sites in their promoter regions and are directly regulated by canonical Wnt/ b-catenin signaling.12 These results have established that bcatenin is a master regulator controlling the expression of all RAS components in the kidneys.

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Klotho Depletion Contributes to Increased Inflammation in Kidney of the db/db Mouse Model of Diabetes via RelA (Serine)536 Phosphorylation

Cited by 210 publications

References 48 publications

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

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

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

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