Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence

Quimby, Jessica M.; Maranon, David G.; Battaglia, Christine L. R.; McLeland, Shannon; Brock, William T; Bailey, Susan M.

doi:10.1152/ajprenal.00527.2012

Cited by 32 publications

(38 citation statements)

References 48 publications

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“…Telomere length has been evaluated in renal (proximal (PTC) and distal tubule), hepatic and dermal tissue from cats with CKD, geriatric and young control cats by telomere flurescence in-situ hybridization with immunostaining (TELI-FISH) in addition to evaluation of SABG. 22 Telomere shortening was evident in PTC of geriatric cats with CKD compared to age matched and young controls despite no difference in telomere length in skin or liver from the same groups. 22 Significantly increased staining for SABG was also found in renal tissue from cats with CKD compared to the young controls although the difference between geriatric control cats was not significant.…”

Section: Ageing and The Kidneymentioning

confidence: 89%

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

Jepson

2016

Veterinary Clinics of North America: Small Animal Practice

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Abstract:In cats with chronic kidney disease (CKD), the most common histopathological finding is tubulointerstitial inflammation and fibrosis. However, these changes reflect a non-specific response of the kidney to any inciting injury. The risk of development of CKD in a patient is likely to reflect genetic predispositions, ageing, environmental and individual factors that influence decline in renal function over the course of a cat's life. However, there is still relatively little information about exactly which risk factors predispose a cat to develop CKD and these will be explored. Whilst many cats diagnosed with CKD have stable disease for many years, some cats show overtly progressive disease.

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Section: Ageing and The Kidneymentioning

confidence: 89%

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

Jepson

2016

Veterinary Clinics of North America: Small Animal Practice

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“…Our measurement strategy produced small variation (less than 5%) across tests, indicating very high test-retest reliability. The fluorescence measurement procedure used in the current study was also externally validated in our previous research of chronic kidney disease in felines (75), where parallel measurements of telomere length were taken from a control cell line (or cell type) using both microbeads and cell type controls, and thereby arriving at satisfactorily reproducible telomere measurements in all experiments.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

“…The value of microscopy-based techniques for evaluation of telomere length on a cell-by-cell basis has been effectively demonstrated (73)(74)(75)(76)(77). We developed an innovative approach for assessment of telomere length that combined telomere-fluorescence in situ hybridization (TEL-FISH) (73) using a modified protocol to collect and process the obtained samples (78), with 3D reconstruction of individual cell nuclei to facilitate analysis of all visible telomere signals in the entire extension of sampled cells, rather than just a fraction (presumably the longest) of them (75). Our approach allowed us to evaluate the length of hundreds of thousands of individual telomeres in a single class of putative buccal basal stem or progenitor cells, greatly improving the specificity and quantification of telomere length, including the important ability to define distributions of the shortest telomeres (76,77).…”

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confidence: 99%

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Stress and telomere shortening among central Indian conservation refugees

Zahran

Snodgrass

Maranon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people-the Sahariya-who were displaced (between 1998 and 2002) from their ancestral homes in a central Indian wildlife sanctuary. In this setting, we examined adult populations in two representative villages, one relocated to accommodate the introduction of Asiatic lions into the sanctuary (n = 24 individuals), and the other newly isolated in the sanctuary buffer zone after their previous neighbors were moved (n = 22). Our research strategy combined physical stress measures via the salivary analytes cortisol and α-amylase with self-assessments of psychosomatic stress, ethnographic observations, and telomere length assessment [telomere-fluorescence in situ hybridization (TEL-FISH) coupled with 3D imaging of buccal cell nuclei], providing high-resolution data amenable to multilevel statistical analysis. Consistent with expectations, we found significant associations between each of our stress measures-the two salivary analytes and the psychosomatic symptom survey-and telomere length, after adjusting for relevant behavioral, health, and demographic traits. As the first study (to our knowledge) to link stress to telomere length in a non-WEIRD population, our research strengthens the case for stress-induced telomere shortening as a pancultural biomarker of compromised health and aging.telomeres | stress | India | indigenous peoples | human displacement P sychosocial stress is associated with elevated risk for a range of human diseases and curtailment of human life expectancy (1-16). Telomeres-repetitive and stabilizing features of chromosomal termini that cap and protect them-have also been shown to be associated with aging and disease (17)(18)(19). Telomere length erodes normally with cell division and generally with aging, triggering cellular senescence once telomere length eclipses a threshold, contributing to tissue degeneration and organ decline with longevity (20-25). Given evidence that stress can elevate the risk of human mortality, and that premature telomere shortening can serve as a proxy for increased risk of disease and mortality, it is reasonable to posit that stress is also associated with telomere shortening (23,26,27). Indeed, research provides evidence of telomere shortening in a range of stress-inducing life situations, including among primary caregivers of chronically ill children and Alzheimer's patients (28, 29), children spending more time in orphanages or experiencing other forms of neglect and adversity (30-32), women suffering from intimate partner violence (33), patients suffering from stress-related mood disorders (34, 35), and...

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“…22,23 CKD is similarly associated with cellular senescence, which contributes to vascular calcification in CKD. 21,24 Acidosis is a common complication in klotho-hypomorphic mice and patients with CKD. 25,26 The pH is a major determinant of the solubility of hydroxyapatite and low pH prevents the precipitation of calcium and phosphate by increasing their solubility.…”

mentioning

confidence: 99%

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

Leibrock¹,

Alesutan²,

Voelkl³

et al. 2015

Journal of the American Society of Nephrology

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Klotho, a cofactor in suppressing 1,25(OH) 2 D 3 formation, is a powerful regulator of mineral metabolism. Klotho-hypomorphic mice (kl/kl) exhibit excessive plasma 1,25(OH) 2 D 3 , Ca 2+ , and phosphate concentrations, severe tissue calcification, volume depletion with hyperaldosteronism, and early death. Calcification is paralleled by overexpression of osteoinductive transcription factor Runx2/Cbfa1, Alpl, and senescenceassociated molecules Tgfb1, Pai-1, p21, and Glb1. Here, we show that NH 4 Cl treatment in drinking water (0.28 M) prevented soft tissue and vascular calcification and increased the life span of kl/kl mice .12-fold in males and .4-fold in females without significantly affecting extracellular pH or plasma concentrations of 1,25(OH) 2 D 3 , Ca 2+ , and phosphate. NH 4 Cl treatment significantly decreased plasma aldosterone and antidiuretic hormone concentrations and reversed the increase of Runx2/Cbfa1, Alpl, Tgfb1, Pai-1, p21, and Glb1 expression in aorta of kl/kl mice. Similarly, in primary human aortic smooth muscle cells (HAoSMCs), NH 4 Cl treatment reduced phosphate-induced mRNA expression of RUNX2/CBFA1, ALPL, and senescence-associated molecules. In both kl/kl mice and phosphate-treated HAoSMCs, levels of osmosensitive transcription factor NFAT5 and NFAT5-downstream mediator SOX9 were higher than in controls and decreased after NH 4 Cl treatment. Overexpression of NFAT5 in HAoSMCs mimicked the effect of phosphate and abrogated the effect of NH 4 Cl on SOX9, RUNX2/CBFA1, and ALPL mRNA expression. TGFB1 treatment of HAoSMCs upregulated NFAT5 expression and prevented the decrease of phosphate-induced NFAT5 expression after NH 4 Cl treatment. In conclusion, NH 4 Cl treatment prevents tissue calcification, reduces vascular senescence, and extends survival of klotho-hypomorphic mice. The effects of NH 4 Cl on vascular osteoinduction involve decrease of TGFB1 and inhibition of NFAT5-dependent osteochondrogenic signaling.

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Feline chronic kidney disease is associated with shortened telomeres and increased cellular senescence

Cited by 32 publications

References 48 publications

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

Stress and telomere shortening among central Indian conservation refugees

NH4Cl Treatment Prevents Tissue Calcification in Klotho Deficiency

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