Acute kidney injury induces dramatic p21 up-regulation via a novel, glucocorticoid- activated, p53 independent, pathway.

ACUTE KIDNEY INJURY INDUCES DRAMATIC P21 UP-REGULATION VIA A NOVEL, GLUCOCORTICOID- ACTIVATED, P53 INDEPENDENT, PATHWAY. Am J Physiol Renal Physiol. 2019 Jan 30;: Authors: Zager RA, Johnson AC Abstract P21, a cyclin kinase inhibitor, is acutely up-regulated during AKI and exerts cytoprotective effects. A proposed mechanism is oxidant stress- induced activation of p53, the dominant p21 transcription factor. Glycerol-induced rhabdomyolysis induces profound renal oxidant stress. Hence, we studied this AKI model to determine whether p53 activation corresponds with p21 gene induction, and/or whether alternative mechanism(s) might be involved. CD-1 mice were subjected to glycerol-induced AKI. Either 4 or 18 hrs later, plasma, urinary, and renal cortical p21 protein and mRNA levels were assessed. Renal p53 activation was gauged by measuring both total and activated p53 (p53-serine15p) and by measuring p53 mRNA. Glycerol evoked acute, progressive renal cortical p21 mRNA/ p21 protein increases. Corresponding plasma (~25x) and urinary (~75x) p21 elevations were also observed. Renal cortical p53/p53-ser15p rose 3-4-fold. However, the p53 inhibitor, pifithrin-α, failed to block glycerol-induced p21 gene induction, suggesting an alternative p21 activator might also be at play. To this end, it was established that glycerol AKI: i) dramatically increases plasma (~5x) and urinary (~75x) cortisol levels; ii) the glucocorticoid receptor (GCR) antagon...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research