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

Xiaohui Bian, Tomás P. Griffin, Xiangyang Zhu, Md Nahidul Islam, Sabena M. Conley, Alfonso Eirin, Hui Tang, Paula M. O'Shea, Allyson K. Palmer, Rozalina G. McCoy, Sandra M. Herrmann, Ramila A. Mehta, John R. Woollard, Andrew D. Rule, James L. Kirkland, Tamar Tchkonia, Stephen C. Textor, Matthew D. Griffin, Lilach O. Lerman, La Tonya J. Hickson

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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.

Original languageEnglish (US)
Article numbere000720
JournalBMJ Open Diabetes Research and Care
Volume7
Issue number1
DOIs
StatePublished - Dec 15 2019

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Keywords

  • adipocytokine
  • clinical aspects of diabetes
  • clinical nephrology
  • renal fibrosis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

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