Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

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Abstract

Objective

Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD.

Research design and methods

In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin.

Results

Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r _s=−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r _s=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased.

Conclusions

Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

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Most cited references 42

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IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040.

K. Ogurtsova, J.D. da Rocha Fernandes, Y. Huang … (2017)

To produce current estimates of the national, regional and global impact of diabetes for 2015 and 2040.

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Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.

Paul E. Stevens (2013)

The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of chronic kidney disease (CKD) in adults and children who are not receiving renal replacement therapy. The KDIGO CKD Guideline Development Work Group defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence that had been summarized by an evidence review team. Searches of the English-language literature were conducted through November 2012. Final modification of the guidelines was informed by the KDIGO Board of Directors and a public review process involving registered stakeholders. The full guideline included 110 recommendations. This synopsis focuses on 10 key recommendations pertinent to definition, classification, monitoring, and management of CKD in adults.

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Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

LaTonya J. Hickson, Larissa G.P. Langhi Prata, Shane Bobart … (2019)

Background Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. Methods In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. Findings D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and −12. Interpretation “Hit-and-run” treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. Fund NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.

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Author and article information

Journal

Journal ID (nlm-ta): BMJ Open Diabetes Res Care

Journal ID (iso-abbrev): BMJ Open Diabetes Res Care

Journal ID (hwp): bmjdrc

Journal ID (publisher-id): bmjdrc

Title: BMJ Open Diabetes Research & Care

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2052-4897

Publication date Collection: 2019

Publication date (Electronic): 15 December 2019

Volume: 7

Issue: 1

Electronic Location Identifier: e000720

Affiliations

[1 ] departmentDivision of Nephrology and Hypertension, Department of Medicine , Mayo Clinic , Rochester, Minnesota, USA

[2 ] departmentDepartment of Nephrology , Shengjing Hospital of China Medical University , Shenyang, China

[3 ] departmentCentre for Endocrinology, Diabetes and Metabolism, Saolta University Health Care Group , Galway University Hospitals , Galway, Ireland

[4 ] departmentRegenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre, School of Medicine , National University of Ireland Galway , Galway, Ireland

[5 ] departmentDepartment of Clinical Biochemistry, Saolta University Health Care Group , Galway University Hospitals , Galway, Ireland

[6 ] departmentDivision of Community Internal Medicine, Department of Medicine , Mayo Clinic , Rochester, Minnesota, USA

[7 ] departmentDivision of Geriatric Medicine and Gerontology, Department of Medicine , Mayo Clinic , Rochester, Minnesota, USA

[8 ] departmentDepartment of Biomedical Statistics and Informatics , Mayo Clinic , Rochester, Minnesota, USA

[9 ] departmentRobert and Arlene Kogod Center on Aging , Mayo Clinic , Rochester, Minnesota, USA

[10 ] departmentDepartment of Nephrology, Saolta University Health Care Group , Galway University Hospitals , Galway, Ireland

Author notes

[Correspondence to ] Dr LaTonya J Hickson; hickson.latonya@ 123456mayo.edu

XB and TPG are co-first authors.

Author information

Rozalina G McCoy http://orcid.org/0000-0002-2289-3183

John R Woollard https://orcid.org/0000-0002-3261-7908

Matthew D Griffin https://orcid.org/0000-0002-8701-8056

Lilach O Lerman https://orcid.org/0000-0002-3271-3887

LaTonya J Hickson http://orcid.org/0000-0002-7485-336X

Article

Publisher ID: bmjdrc-2019-000720

DOI: 10.1136/bmjdrc-2019-000720

PMC ID: 6936543

PubMed ID: 31908790

SO-VID: ff492d60-fbd9-4cc5-ac0c-982566a14b5d

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 27 June 2019

Date revision received : 28 September 2019

Date accepted : 23 October 2019

Funding

Funded by: Satellite Healthcare;

Award ID: N/a

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: K23 DK109134

Award ID: R01 DK102325

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Keywords: adipocytokine,clinical aspects of diabetes,clinical nephrology,renal fibrosis

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Keywords: adipocytokine, clinical aspects of diabetes, clinical nephrology, renal fibrosis

Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

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cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 42

IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040.

Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline.

Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease

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