Transcriptional and physiological responses to chronic ACTH treatment by the mouse kidney

Abstract

We investigated the effects on urinary steroid and electrolyte excretion and renal gene expression of chronic infusions of ACTH in the mouse. ACTH caused a sustained increase in corticosteroid excretion; aldosterone excretion was only transiently elevated. There was an increase in the excretion of deoxycorticosterone, a weak mineralocorticoid, to levels of physiological significance. Nevertheless, we observed neither antinatriuresis nor kaliuresis in ACTH-treated mice, and plasma renin activity was not suppressed. We identified no changes in expression of mineralocorticoid target genes. Water turnover was increased in chronic ACTH-treated mice, as were hematocrit and hypertonicity: volume contraction is consistent with high levels of glucocorticoid. ACTH-treated mice exhibited other signs of glucocorticoid excess, such as enhanced weight gain and involution of the thymus. We identified novel ACTH-induced changes in 1) genes involved in vitamin D (Cyp27b1, Cyp24a1, Gc) and calcium (Sgk, Calb1, Trpv5) metabolism associated with calciuria and phosphaturia; 2) genes that would be predicted to desensitize the kidney to glucocorticoid action (Nr3c1, Hsd11b1, Fkbp5); and 3) genes encoding transporters of enzyme systems associated with xenobiotic metabolism and oxidative stress. Although there is evidence that ACTH-induced hypertension is a function of physiological cross talk between glucocorticoids and mineralocorticoids, the present study suggests that the major changes in electrolyte and fluid homeostasis and renal function are attributable to glucocorticoids. The calcium and organic anion metabolism pathways that are affected by ACTH may explain some of the known adverse effects associated with glucocorticoid excess.

Distal Convoluted Tubule

“…In rats, the synthetic glucocorticoid dexamethasone significantly enhanced renal TRPV5 and Calbindin-d28K mRNA and protein abundance, probably to compensate for reduced Ca 2+ reabsorption along proximal tubule and TAL (355). )Restraint stress was reported to increase expression of NCX (209), while chronic treatment of mice with ACTH, which stimulates glucocorticoid secretion, led to increase Calbindin expression, but reduced TRPV5 expression (110). …”

Glucocorticoids and renal Na+ transport: implications for hypertension and salt sensitivity

“…The stimulatory effect of ACTH on aldosterone seems to be transient, but that on deoxycorticosterone sustained (Dunbar et al . ). Finally, ACTH may stimulate renin production in the juxtaglomerular apparatus (Oelkers et al .…”

“…Data are surprisingly scarce but downregulation of renal 11βHSD1 is an adaptive response to either salt loading or increased blood pressure (Dunbar et al . ). Failure to transcriptionally repress the encoding gene, hsd11b1 , contributes to the pathogenesis of salt‐sensitive hypertension.…”

“…Similarly, chronic ACTH infusion into mice increases Na + excretion (Dunbar et al . ) despite the fact that activation of MR and GR promotes Na + reabsorption in the distal tubule (Bailey et al . ).…”

Novel Concepts in the Genesis of Hypertension: Role of LOX-1

“…It is well known that hypertension is associated with increased vascular oxidative stress, although there is an ongoing debate whether oxidative stress is a cause or a result of hypertension [1,2,19]. Oxidative stress has been demonstrated in patients with essential/spontaneous hypertension, renovascular hypertension, malignant hypertension, and pre-eclampsia, as well as in experimental models such as Ang II-mediated hypertension, Dahl saltsensitive hypertension, lead-induced hypertension, obesityassociated hypertension, mineralocorticoid hypertension, aldosterone-provoked hypertension, nitric oxide synthase inhibitor-induced hypertension and cyclosporine-induced hypertension [20][21][22][23][24][25][26][27][28][29][30][31][32]. Oxidative stress may contribute to the generation and/or maintenance of hypertensive state via a number of possible mechanisms.…”