Klotho, Aging, and the Failing Kidney

Buchanan, Sarah; Combet, Emilie; Stenvinkel, Peter; Shiels, Paul G.

doi:10.3389/fendo.2020.00560

Cited by 151 publications

(121 citation statements)

References 196 publications

(274 reference statements)

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“…Furthermore, the aforementioned metabolic and hemodynamic stresses during diabetes and diabetic nephropathy can cause cellular dysfunction and damage and stimulate an inflammatory response and subsequent fibrosis, resulting in renal injury. Pathological processes of diabetic nephropathy resemble kidney injury through cellular senescence [ 7 ], with a shortening of telomeres, DNA damage, epigenetic alterations, changes in protein patterns, mitophagy deficiencies, the downregulation of Klotho expression, inflammation, the activation of profibrotic Wnt/β-catenin signaling, and the accumulation of uremic toxins (e.g., indoxyl sulfate) that further reduce renal Klotho expression and intensify fibrosis [ 8 , 9 , 10 , 11 , 12 ].…”

Section: Diabetes Mellitus and Diabetic Nephropathymentioning

confidence: 99%

“…Type 2 DM develops during the course of a prolonged high-glucose diet and consists of impairments in pancreatic insulin secretion and a lower cellular response to insulin stimulation. These metabolic changes are accompanied by a low-grade inflammatory process in adipose tissue, the liver, and pancreatic islets, in which IL-1β plays a major role [ 12 ]. The prolonged upregulation of IL-1β leads to an increase in serum insulin levels, which promotes glucose uptake by macrophages, which infiltrate the pancreatic tissue, with an upregulation of their proinflammatory activity, including the production of ROS and initiation of the generation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome [ 26 ].…”

Section: Immune Response In Diabetes and Diabetic Nephropathymentioning

confidence: 99%

“…Furthermore, a few studies have evaluated the therapeutic effects of recombinant Klotho and the stimulation of Klotho overexpression (e.g., by calcitriol, peroxisome proliferator-activated receptor γ [ 41 ], substances like pioglitazone [ 7 ] and Klotho gene delivery through a viral vector), which downregulated oxidative stress, ameliorated the high glucose-induced injury of renal glomerular endothelial cells in a model of diabetic nephropathy, suppressed diabetes-induced renal hypertrophy, and exerted other immunotherapeutic effects in diabetic nephropathy [ 12 , 16 , 44 , 59 ]. When podocytes that were cultured in a medium with high glucose concentrations were incubated with high Klotho protein levels, podocyte injury was significantly attenuated compared with podocytes that were not treated with Klotho.…”

Section: Klotho May Serve As a Key Molecule In Immunotherapy Of DImentioning

confidence: 99%

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Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

Typiak

Piwkowska

2021

IJMS

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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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Section: Diabetes Mellitus and Diabetic Nephropathymentioning

confidence: 99%

Section: Immune Response In Diabetes and Diabetic Nephropathymentioning

confidence: 99%

Section: Klotho May Serve As a Key Molecule In Immunotherapy Of DImentioning

confidence: 99%

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Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

Typiak

Piwkowska

2021

IJMS

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“…α -Klotho not only functions as one of the regulators of mineral homeostasis but also exerts pleiotropic biological effects including antioxidative stress, antiapoptosis, and antiaging [ 87 , 88 ]. α -Klotho is expressed in multiple tissues; however, the strongest expression is in the kidney [ 89 ].…”

Section: Uremic Toxins and Kidney Functionmentioning

confidence: 99%

Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation

Wojtaszek

Ołdakowska‐Jedynak

Kwiatkowska

et al. 2021

Oxidative Medicine and Cellular Longevity

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Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular disease (CVD), and approximately half of all deaths among patients with CKD are a direct result of CVD. The premature cardiovascular disease extends from mild to moderate CKD stages, and the severity of CVD and the risk of death increase with a decline in kidney function. Successful kidney transplantation significantly decreases the risk of death relative to long-term dialysis treatment; nevertheless, the prevalence of CVD remains high and is responsible for approximately 20-35% of mortality in renal transplant recipients. The prevalence of traditional and nontraditional risk factors for CVD is higher in patients with CKD and transplant recipients compared with the general population; however, it can only partly explain the highly increased cardiovascular burden in CKD patients. Nontraditional risk factors, unique to CKD patients, include proteinuria, disturbed calcium, and phosphate metabolism, anemia, fluid overload, and accumulation of uremic toxins. This accumulation of uremic toxins is associated with systemic alterations including inflammation and oxidative stress which are considered crucial in CKD progression and CKD-related CVD. Kidney transplantation can mitigate the impact of some of these nontraditional factors, but they typically persist to some degree following transplantation. Taking into consideration the scarcity of data on uremic waste products, oxidative stress, and their relation to atherosclerosis in renal transplantation, in the review, we discussed the impact of uremic toxins on vascular dysfunction in CKD patients and kidney transplant recipients. Special attention was paid to the role of native and transplanted kidney function.

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“…Klotho is a transmembrane protein, mainly expressed in the proximal and distal tubular cells [28]. CKD patients present reduced levels of klotho.…”

Section: Klothomentioning

confidence: 99%

New Potential Biomarkers for Chronic Kidney Disease Management—A Review of the Literature

Lousa

Reis

Beirão

et al. 2020

IJMS

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The prevalence of chronic kidney disease (CKD) is increasing worldwide, and the mortality rate continues to be unacceptably high. The biomarkers currently used in clinical practice are considered relevant when there is already significant renal impairment compromising the early use of potentially successful therapeutic interventions. More sensitive and specific biomarkers to detect CKD earlier on and improve patients’ prognoses are an important unmet medical need. The aim of this review is to summarize the recent literature on new promising early CKD biomarkers of renal function, tubular lesions, endothelial dysfunction and inflammation, and on the auspicious findings from metabolomic studies in this field. Most of the studied biomarkers require further validation in large studies and in a broad range of populations in order to be implemented into routine CKD management. A panel of biomarkers, including earlier biomarkers of renal damage, seems to be a reasonable approach to be applied in clinical practice to allow earlier diagnosis and better disease characterization based on the underlying etiologic process.

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Klotho, Aging, and the Failing Kidney

Cited by 151 publications

References 196 publications

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation

New Potential Biomarkers for Chronic Kidney Disease Management—A Review of the Literature

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