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Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling

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Abstract

Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.

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Data availability

Data supporting this study are included within the article.

Abbreviations

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

BUN:

Blood urea nitrogen

CKD:

Chronic kidney disease

CK-MB:

Creatine kinase-MB

CRS:

Cardiorenal syndrome

CVD:

Cardiovascular disease

ECM:

Extracellular matrix

EF:

Ejection fraction

ELISA:

Enzyme-linked immunosorbent assay

ESRD:

End-stage renal disease

FS:

Fractional shortening

H & E:

Hematoxylin and eosin stain

HDACs:

Histone deacetylases

ILs:

Interleukins

LDH:

Lactate dehydrogenase

LVAWd:

Left-ventricular end-diastolic anterior wall thickness

LVAWs:

Left-ventricular end-systolic anterior wall thickness

LVH:

Left-ventricular hypertrophy

LVPWd:

Left-ventricular end-diastolic posterior wall thickness

LVPWs:

Left-ventricular end-systolic posterior wall thickness

MT:

Masson’s trichrome stain

NF-κB (p65):

Nuclear factor-kappa B (p65)

qRT-PCR:

Quantitative real-time polymerase chain reaction

RIC:

Ricolinostat

STAT3:

Signal transducer and activator of transcription 3

TGF-β:

Transforming growth factor-beta

TNF-α:

Tumor necrosis factor-alpha

UUO:

Unilateral ureteral obstruction

VAL:

Valsartan

WGA:

Wheat germ agglutinin stain

α-SMA:

Alfa-smooth muscle actin

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Acknowledgements

The study is supported by a Start-Up Research Grant in Life Sciences (Grant No. SRG/2021/000428) of the Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, New Delhi.

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Authors

Contributions

Sourav Kundu and Shobhit Gairola: conceptualization, methodology, formal analysis, investigation, writing—original draft. Smriti Verma and Madhav Nilakanth Mugale: methodology (histopathology studies), formal analysis, and investigation. Bidya Dhar Sahu: conceptualization, supervision, funding acquisition, and writing—review and editing.

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Correspondence to Bidya Dhar Sahu.

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The animal study protocol was reviewed and approved by the Institutional Animal Ethics Committee (IAEC) of the NIPER Guwahati (Approval No. NIPER/PC/2022/04) and performed in accordance with the Committee for Control and Supervision of Experiments on Animals (CCSEA), Government of India.

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Kundu, S., Gairola, S., Verma, S. et al. Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling. Basic Res Cardiol (2024). https://doi.org/10.1007/s00395-024-01056-y

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