Science Spotlight

Protective p21 propagation requires glucocorticoids

From the Zager Laboratory, Clinical Research Division

Acute kidney injury (AKI) can be caused by inadequate blood flow to the kidneys or by damage from muscle breakdown products released into the bloodstream following severe muscle injury. Following AKI, levels of p21, a protein with cytoprotective effects, increase in the kidneys. p21 can exert protection by arresting the cell cycle as it is a cyclin kinase inhibitor. Cell cycle arrest allows cells to repair damage.  The dominant transcription factor controlling p21 levels is p53. Oxidant stress, common in AKI, causes an increase in activated p53. As such, it was thought that increased p21 after AKI is a result of activation of a p53-dependent pathway. The laboratory of Dr. Richard Zager wanted to further study this likely pathway with hopes of improving the understanding and treatment of AKI.

Surprisingly, in a study published in the American Journal of Physiology-Renal Physiology, Dr. Zager found that the p21 increase noted in AKI is independent of activated p53 levels. The lab used a preclinical mouse model of glycerol-induced AKI. In this model, they noticed elevated levels of p21 in the plasma, urine, and kidney after AKI. However, p21 increase did not correlate to an increase in p53. To further confirm that p21 following AKI is not reliant on p53, the researchers administered pifithrin-α, a p53 inhibitor, which did not prevent the increase in p21.

Acute kidney injury leads to a release of cortisol by the adrenal gland which increases p21 levels in multiple organs. This p21 increase may also be triggered by doses of corticosteroids commonly used in cancer treatments.
Acute kidney injury leads to a release of cortisol by the adrenal gland which increases p21 levels in multiple organs. This p21 increase may also be triggered by doses of corticosteroids commonly used in cancer treatments. Image provided by Dr. Richard Zager.

After discovering that this pathway was p53-independent, Dr. Zager reasoned that increased p21 might be a response to inflammation. To test this theory, the authors administered dexamethasone, a potent anti-inflammatory agent classified as a glucocorticoid. While they found that dexamethasone lowered inflammation as expected, but they were surprised to discover that it drastically raised p21 levels. This p21 increase occurred in both normal mice and mice with glycerol-induced AKI. They also found that after AKI, there was an increase in plasma and urinary cortisol, an endogenous glucocorticoid. To show that p21 levels are increasing as a direct response to glucocorticoids, they administered mifepristone, a glucocorticoid receptor antagonist. Mifepristone blocked the increase of p21 while having no effect on p53 levels, showing that the p21 increase is through a glucocorticoid-dependent pathway. “It’s a novel observation that glucocorticoids can trigger p21 going up,” Dr. Zager said. “The other thing that’s really surprising is that the p21 got into the blood. It could be coming out of the kidney or, since cortisol will work everywhere, it could be coming out of other organs as well.” In a previous study, the Zager lab showed that p21 was upregulated in the heart and brain after kidney injury. “It may very well be that AKI is causing this cortisol increase which is then triggering p21 in multiple organs.”

Beyond inflammation, glucocorticoids are involved in regulating various immune and metabolic pathways. They are used to treat multiple diseases and disorders, including some cancers and graft-versus-host disease. Because of their broad involvement, Dr. Zager wants to focus future research on what other pathways cortisol might be affecting in AKI. “It's known that p21 causes transient growth arrest,” Dr. Zager said. “Nobody has discovered that cortisol does this to p21. The thing that's interesting is that if it’s doing this to p21 then it’s probably doing lots of things to other signaling pathways.”

 

This work was supported by Renibus Therapeutics and the National Institutes of Health.

Fred Hutch/UW Cancer Consortium member Richard Zager contributed to this work.

Zager RA, Johnson ACM. 2019. Acute kidney injury induces dramatic p21 upregulation via a novel, glucocorticoid-activated, pathway. Am J Physiol Renal Physiol. 2019 Apr 1;316(4):F674-F681. doi: 10.1152/ajprenal.00571.2018. Epub 2019 Jan 30.

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