DNA damage and p21WAF1/CIP1/SDI1 in experimental injury of the rat adrenal cortex and trauma-associated damage of the human adrenal cortex

Abstract

In vivo models are needed to study the reactions of tissues to DNA damage, such as the induction of the cyclin‐dependent kinase inhibitor p21, indicating potential repair of the damage, versus apoptosis, indicating the elimination of the damaged cells. Damage to DNA occurs in tissues during shock, sepsis, and other critical medical conditions. Previous studies have found evidence of damage to the cortex of adrenal glands from organ donors who had undergone severe trauma prior to death. The present experiment studied rats under experimental interventions of clinical relevance to patients with conditions that put them at risk for damage to the adrenal glands. These interventions comprised ischaemia and reperfusion injury, sepsis following caecal ligation and puncture, acute pancreatitis, and administration of chemical agents (zymosan and acrylonitrile). All the interventions caused an increase in p21 mRNA as assessed by northern blotting and in situ hybridization. Increased nuclear p21 protein was shown by immunohistochemistry. All the interventions caused damage to DNA, as shown by labelling of available 3′ termini of single‐strand breaks with terminal transferase. The number of cells undergoing apoptosis, visualized by ligation of a hairpin oligonucleotide probe to double‐strand breaks in DNA, was much lower. In rat adrenal glands, apoptotic cells were infrequent under all the conditions studied. They were more abundant in human organ donor adrenal glands that were previously shown to have extensive DNA damage accompanied by induction of p21. The similarity of the effects of a wide variety of surgical interventions and chemical agents suggest a common pathophysiological mechanism which is not specific to the initiating injury. Experimental injury of the rat adrenal cortex provides a model for investigating the role of organ DNA damage and of mediators of the response to DNA damage, such as p21. Copyright © 1999 John Wiley & Sons, Ltd.

Gene expression profile in rat adrenal zona glomerulosa cells stimulated with aldosterone secretagogues

“…Cdkn1a (also known as p21, Cip1, Waf1, Sdi1, Cap20, p21Cip1) has been implicated in cell cycle regulation, through inhibition of the cyclin-dependent protein kinase and DNA replication, but it is also associated with transcriptional regulation, apoptosis, and senescence (6,7,70). Cdkn1a is expressed in the human and rodent adrenal gland (11,12). Cdkn1a expression is highly upregulated by adrenocortical cell dispersion and culture in vitro (72) and adrenal gland ischemia/reperfusion, sepsis, and acute pancreatitis in vivo (11,12).…”

Relationship of p21WAF1/CIP1/SDI1 to cell proliferation in primary cultures of adrenocortical cells

“…On the other hand, there clearly is a role for p21 as a response to DNA damage in adrenocortical cells, both in culture and in vivo. In the intact adrenal gland, DNA damage rapidly increases p21 throughout the adrenal cortex, but this is not associated either positively or negatively with cell division (14,15).…”

Human Adrenal Androgens: Regulation of Biosynthesis and Role in Estrogen-Responsive Breast Cancer in a Mouse Model

“…We observed that DNA damage, p53 and p21 could be induced in the rat adrenal gland by ischemia/reperfusion and by sepsis Didenko et al, 1999). A likely common element in injury of the adrenal gland is damage to the microvasculature.…”

“…In this laboratory we studied the susceptibility of adrenocortical cells in vivo to DNA damage and apoptosis under varying conditions Didenko et al, 1999). In adrenocortical cells in glands from some organ donors, evidence of DNA damage was accompanied by immunoreactive p53 and p21 WAF1 P1…”