Research Paper Volume 15, Issue 20 pp 11532—11545
Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α–FNDC5 axis
- 1 Division of Nephrology, Department of Internal Medicine, Cardinal Tien Hospital, New Taipei City 231, Taiwan
- 2 School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
- 3 Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan
- 4 Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
- 5 Department of Medical Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- 6 Department of Internal Medicine, Division of Nephrology, Shuang Ho Hospital, School of Medicine, College of Medicine, Taipei Medical University, New Taipei City 110, Taiwan
- 7 TMU Research Centre of Urology and Kidney, Taipei Medical University, New Taipei City 110, Taiwan
- 8 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, New Taipei City 110, Taiwan
- 9 Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 110, Taiwan
- 10 Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
- 11 Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 243, Taiwan
Received: December 19, 2022 Accepted: September 8, 2023 Published: October 23, 2023
https://doi.org/10.18632/aging.205141How to Cite
Copyright: © 2023 Hou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Objective: Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD.
Materials and Methods: The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson’s trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting.
Results: Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively (p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 μM and 23.19 ± 33.28 μM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139–0.457, p < 0.05) and 0.733 (95% CI: 0.575–0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-β signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose–dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells.
Conclusion: IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α–FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α–FNDC5 axis in skeletal muscle.
Abbreviations
CKD: chronic kidney disease; ESRD: end-stage renal disease; FNDC5: fibronectin type III domain containing 5; GADPH: glyceraldehyde 3-phosphate dehydrogenase; IS: indoxyl sulfate; N/S: normal saline; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; NO66: nucleolar protein 66; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K/Akt/AMPK: phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homologue/AMP-activated protein kinase; PPARγ: peroxisome proliferator-activated receptor gamma; RSV: resveratrol; SMAD: small mothers against decapentaplegic homolog; TGFβ: transforming growth factor beta.