Early vascular aging in chronic kidney disease: focus on microvascular maintenance, senescence signature and potential therapeutics

Samsul Arefin ¹, Neja Mudrovcic ¹, Sam Hobson ¹

¹Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
²Department of Biosciences and Nutrition, Karolinska Institutet, Sweden.
³Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
⁴Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linkoping, Sweden.
⁵Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁶Division of Rheumatology, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
⁷Department of Clinical Sciences, Danderyds Hospital, Karolinska Institutet; Department of Surgery, Ersta Hospital, Stockholm, Sweden.
⁸Laboratory of Translational Research, University of Torino, Italy.
⁹Nephrology and Dialysis Unit, ASL CN1, Cuneo, Italy.
¹⁰Department of Translational Medicine, Nephrology and Kidney Transplantation Unit, University of Piemonte Orientale (UPO), Italy.

⁰Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Translational Research : the Journal of Laboratory and Clinical Medicine +

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November 7, 2024

View abstract on PubMed

Summary

Uremic toxins in end-stage kidney disease (ESKD) promote vascular aging and dysfunction by inducing cellular senescence. Senolytic agents show promise in reversing these changes, potentially reducing cardiovascular complications in ESKD patients.

Area Of Science

Vascular Biology
Nephrology
Gerontology

Background

Chronic kidney disease (CKD) significantly increases cardiovascular mortality.
End-stage kidney disease (ESKD) is associated with early vascular aging (EVA) and microvascular dysfunction.
Uremic toxins are hypothesized to instigate a senescent phenotype contributing to vascular complications.

Purpose Of The Study

To investigate the role of uremic toxins and cellular senescence in early vascular aging (EVA) in ESKD patients.
To compare in vivo and ex vivo vascular function and structure between ESKD patients and controls.
To assess the potential of senolytic agents in mitigating vascular abnormalities in ESKD.

Main Methods

Studied 82 ESKD patients and 70 non-CKD controls using in vivo and ex vivo approaches.
Measured endothelial and smooth muscle function, vascular stiffness, and senescence markers.
Exposed uremic arteries to uremic toxins and treated with senolytic agents (Dasatinib + Quercetin).

Main Results

ESKD patients showed increased microvascular stiffness in vivo.
Ex vivo studies revealed impaired endothelial function and increased stiffness in ESKD, linked to uremic toxins.
Uremic arteries exhibited a 'senescence signature' with elevated senescence markers and reduced regenerative markers.
Senolytic treatment reversed senescence markers and altered extracellular vesicle profiles ex vivo.
Observed sex differences in vascular abnormalities.

Conclusions

The uremic microvasculature exhibits a senescence signature contributing to EVA and cardiovascular risks in ESKD.
Uremic toxins impair endothelial function by reducing nitric oxide and hyperpolarizing factor.
Senolytic therapy presents a potential therapeutic strategy for vascular complications in ESKD.

Keywords:

Chronic kidney disease Early vascular aging Senescence Vascular function

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