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Senescence Marker Activin A Is Increased in Human Diabetic Kidney Disease: Association With Kidney Function and Potential Implications for Therapy

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, etc.

BMJ Open Diabetes Res Care. 2019 Dec 15;7(1):e000720.

PMID: 31908790

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 (rs=-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 (rs=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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248740	Activin A human			Price

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