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Plasma and urinary p21: potential biomarkers of AKI and renal aging
Ali C Johnson1, Richard A Zager1,2
1The Clinical Research Division, Fred Hutchinson Cancer Research Center , Seattle, Washington.
Abstract:
p21 is upregulated in renal tubules in response to acute kidney injury ( AKI). and localizes in the nucleus, where it induces cell cycle arrest (CCA). These events can mitigate early injury but can also facilitate the onset of the degenerative cell senescence/"aging" process. Hence, we asked the following: 1) can AKI-induced p21 upregulation be gauged by plasma and/or urinary p21 assay; 2) might p21 serve as an AKI/CCA biomarker; and 3) does p21 accumulate during normal renal aging, and might plasma p21 reflect this process? Mice were subjected to either ischemia-reperfusion (I/R) or nephotoxic (maleate) AKI. Renal cortical p21 expression (protein, mRNA) was assessed 2-18 h later and contrasted with plasma/urine p21 concentrations (ELISA). p21 mRNA/protein levels were also measured in aging mice (2, 12, 24 mo). AKI induced marked, progressive, increases in renal cortical p21 mRNA and protein levels. These changes were marked by acute (within 2-4 h) and profound increases (up to 200×) in both plasma and urine p21 concentrations. Renal I/R also activated p21 gene expression in extrarenal organs (heart, brain), consistent with so-called "organ cross talk". p21 efflux from damaged cells was confirmed with studies of hypoxia-injured, isolated proximal tubules. Aging was associated with progressive renal cortical p21 expression, which correlated ( r, 0.83) with rising plasma p21 concentrations. We concluded that 1) during AKI, renal p21 increases can be gauged by either plasma or urine p21 assay, serving as potentially useful AKI/CCA biomarkers; 2) AKI can activate p21 in extrarenal organs; and 3) plasma p21 levels may provide an index of the renal/systemic aging process.
Insights
Plasma and urine p21 levels can indicate acute kidney injury (AKI) and cell cycle arrest (CCA). Rising plasma p21 may also reflect normal renal and systemic aging processes.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- p21 upregulation in renal tubules follows acute kidney injury (AKI), inducing cell cycle arrest (CCA).
- This process may mitigate early injury but can also promote cellular senescence (aging).
Purpose of the Study:
- To determine if plasma and urine p21 assays can measure AKI-induced p21 upregulation.
- To investigate p21's potential as a biomarker for AKI and CCA.
- To assess p21 accumulation during renal aging and its reflection in plasma levels.
Main Methods:
- Mice underwent ischemia-reperfusion or maleate-induced AKI.
- Renal cortical p21 expression (mRNA, protein) and plasma/urine p21 concentrations were measured.
- p21 levels were also assessed in aging mice (2, 12, 24 months).
Main Results:
- AKI significantly increased renal cortical p21 mRNA and protein levels.
- Plasma and urine p21 concentrations rose acutely (2-4 hours) and profoundly (up to 200×) post-AKI.
- Aging correlated with increased renal p21 expression and rising plasma p21 levels (r=0.83).
- AKI induced p21 expression in extrarenal organs (heart, brain).
Conclusions:
- Plasma or urine p21 assays can effectively gauge renal p21 increases during AKI, serving as potential biomarkers.
- AKI can trigger p21 activation in organs beyond the kidney.
- Plasma p21 levels may indicate renal and systemic aging.
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