Deoxycorticosterone acetate

Deoxycorticosterone acetate is a steroid hormone used for intramuscular injection for replacement therapy of the adrenocortical steroid.

Resting Afferent Renal Nerve Discharge and Renal Inflammation: Elucidating the Role of Afferent and Efferent Renal Nerves in Deoxycorticosterone Acetate Salt Hypertension.[Pubmed:27698066]

Hypertension. 2016 Dec;68(6):1415-1423.

Renal sympathetic denervation (RDNx) has emerged as a novel therapy for hypertension; however, the therapeutic mechanisms remain unclear. Efferent renal sympathetic nerve activity has recently been implicated in trafficking renal inflammatory immune cells and inflammatory chemokine and cytokine release. Several of these inflammatory mediators are known to activate or sensitize afferent nerves. This study aimed to elucidate the roles of efferent and afferent renal nerves in renal inflammation and hypertension in the Deoxycorticosterone acetate (DOCA) salt rat model. Uninephrectomized male Sprague-Dawley rats (275-300 g) underwent afferent-selective RDNx (n=10), total RDNx (n=10), or Sham (n=10) and were instrumented for the measurement of mean arterial pressure and heart rate by radiotelemetry. Rats received 100-mg DOCA (SC) and 0.9% saline for 21 days. Resting afferent renal nerve activity in DOCA and vehicle animals was measured after the treatment protocol. Renal tissue inflammation was assessed by renal cytokine content and T-cell infiltration and activation. Resting afferent renal nerve activity, expressed as a percent of peak afferent nerve activity, was substantially increased in DOCA than in vehicle (35.8+/-4.4 versus 15.3+/-2.8 %Amax). The DOCA-Sham hypertension (132+/-12 mm Hg) was attenuated by approximately 50% in both total RDNx (111+/-8 mm Hg) and afferent-selective RDNx (117+/-5 mm Hg) groups. Renal inflammation induced by DOCA salt was attenuated by total RDNx and unaffected by afferent-selective RDNx. These data suggest that afferent renal nerve activity may mediate the hypertensive response to DOCA salt, but inflammation may be mediated primarily by efferent renal sympathetic nerve activity. Also, resting afferent renal nerve activity is elevated in DOCA salt rats, which may highlight a crucial neural mechanism in the development and maintenance of hypertension.

Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate-salt hypertension.[Pubmed:27663860]

FASEB J. 2017 Jan;31(1):72-84.

The aim of this study was to investigate the in vivo role of angiotensin II type 1a (AT1a) receptor in renal damage as a result of hypertension by using transgenic mice with AT1a receptor gene disruption. Transgenic mice that express human liver-type fatty acid binding protein (L-FABP) with or without disruption of the AT1a receptor gene (L-FABP(+/-) AT1a(-/-), and L-FABP(+/-) AT1a(+/+), respectively) were used with urinary L-FABP as an indicator of tubulointerstitial damage. Those female mice were administered subcutaneously Deoxycorticosterone acetate (DOCA)-salt tablets plus drinking water that contained 1% saline for 28 d after uninephrectomy. In L-FABP(+/-) AT1a(+/+) mice that received DOCA-salt treatment, hypertension was induced and slight expansion of glomerular area, glomerular sclerosis, and tubulointerstitial damage were observed. In L-FABP(+/-) AT1a(-/-) mice that received DOCA-salt treatment, hypertension was similarly induced and the degree of glomerular damage was significantly more severe than in L-FABP(+/-) AT1a(+/+)-DOCA mice. Urinary L-FABP levels were significantly higher in L-FABP(+/-) AT1a(-/-)-DOCA mice compared with those in L-FABP(+/-) AT1a(+/+)-DOCA mice. Hydralazine treatment significantly attenuated renal damage that was found in L-FABP(+/-) AT1a(-/-)-DOCA mice along with a reduction in blood pressure. In summary, activation of the AT1a receptor may contribute to maintenance of the glomerular structure against hypertensive renal damage.-Hisamichi, M., Kamijo-Ikemori, A., Sugaya, T., Ichikawa, D., Natsuki, T., Hoshino, S., Kimura, K., Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by Deoxycorticosterone acetate-salt hypertension.

Activation of TRPV4 by dietary apigenin antagonizes renal fibrosis in deoxycorticosterone acetate (DOCA)-salt-induced hypertension.[Pubmed:28143892]

Clin Sci (Lond). 2017 Apr 1;131(7):567-581.

Hypertension-induced renal fibrosis contributes to the progression of chronic kidney disease, and apigenin, an anti-hypertensive flavone that is abundant in celery, acts as an agonist of transient receptor potential vanilloid 4 (TRPV4). However, whether apigenin reduces hypertension-induced renal fibrosis, as well as the underlying mechanism, remains elusive. In the present study, the Deoxycorticosterone acetate (DOCA)-salt hypertension model was established in male Sprague-Dawley rats that were treated with apigenin or vehicle for 4 weeks. Apigenin significantly attenuated the DOCA-salt-induced structural and functional damage to the kidney, which was accompanied by reduced expression of transforming growth factor-beta1 (TGF-beta1)/Smad2/3 signaling pathway and extracellular matrix proteins. Immunochemistry, cell-attached patch clamp and fluorescent Ca(2+) imaging results indicated that TRPV4 was expressed and activated by apigenin in both the kidney and renal cells. Importantly, knockout of TRPV4 in mice abolished the beneficial effects of apigenin that were observed in the DOCA-salt hypertensive rats. Additionally, apigenin directly inhibited activation of the TGF-beta1/Smad2/3 signaling pathway in different renal tissues through activation of TRPV4 regardless of the type of pro-fibrotic stimulus. Moreover, the TRPV4-mediated intracellular Ca(2+) influx activated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, which inhibited the TGF-beta1/Smad2/3 signaling pathway. In summary, dietary apigenin has beneficial effects on hypertension-induced renal fibrosis through the TRPV4-mediated activation of AMPK/SIRT1 and inhibition of the TGF-beta1/Smad2/3 signaling pathway. This work suggests that dietary apigenin may represent a promising lifestyle modification for the prevention of hypertension-induced renal damage in populations that consume a high-sodium diet.

[Tetrahydrobiopterin improves left ventricular diastolic function possibly through upregulating phosphorylated protein kinase B expression in hypertensive mice induced by deoxycorticosterone acetate].[Pubmed:27667273]

Zhonghua Xin Xue Guan Bing Za Zhi. 2016 Sep 24;44(9):759-765.

Objective: To investigate whether tetrahydrobiopterin (BH4) could improve left ventricular diastolic function through phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway in hypertensive mice. Methods: Ten-week-old male C57BL/6 mice were used to establish the Deoxycorticosterone acetate (DOCA)-salt hypertensive model, age matched Sham mice serve as the controls. Mice were divided into four groups: Sham(n=20), Sham+ BH4 (n=20), DOCA (n=22), and DOCA+ BH4 (n=22). On the 14 days after surgery, mice in Sham+ BH4 and DOCA+ BH4 groups received BH4 (0.1 ml/10 g) supplement for 7 days, while mice in Sham and DOCA groups were given equal volume of normal saline.The blood pressure measurements were performed 7 days later.Hemodynamic and echocardiographic parameters were used to assess left ventricular functions.High performance liquid chromatography (HPLC) analysis was used to measure cardiac biopterins BH4 and BH2.The phosphorylated phospholamban (p-PLB) was detected by immunohistochemical staining. PI3K, Akt and phosphorylated Akt were assayed with Western blot analysis. Results: (1) The systolic and diastolic blood pressure of DOCA group were significantly higher than control group (P<0.05). Compared with DOCA group, the systolic blood pressure was lower in DOCA+ BH4 mice (P=0.027). Diastolic blood pressure was similar between the groups. (2) Compared with Sham group, the left ventricular diastolic function indexes such as mitral annulus velocity (E') and E'/A'ratio were significantly lower, while the E/ E'ratio was significantly higher(P<0.05)in DOCA mice. The E/ E'ratio of DOCA+ BH4 group was significantly lower than that of DOCA group (P<0.05). Compared with Sham group, the left ventricular end-diastolic pressure (LVEDP), left ventricular end-diastolic pressure volumetric coefficient (EDPVR) and left ventricular relaxation time constant Tau index were significantly higher in DOCA mice (P=0.002, 0.011 and 0.016, respectively). The EDPVR and Tau index were significantly lower in DOCA+ BH4 group than in DOCA group (P<0.05). (3) Compared with Sham group, the myocardial contents of BH4 and BH2 were significantly lower in DOCA mice (P<0.05). The BH4 levels and BH4/BH2 ratio were significantly higher in Sham+ BH4 and DOCA+ BH4 groups than in the DOCA group (P<0.05), but the BH2 levels were similar between groups. (4) The cGMP content, SOD activity and NO content in the left ventricular myocardial tissue were significantly lower (P<0.05), while the MDA content was significantly higher in DOCA mice than in Sham mice.The NO content and SOD activity in DOCA+ BH4 groups were significantly higher than in the DOCA group (P<0.05). (5) Compared with DOCA group, the expression of p-PLB was significantly higher in Sham mice and lower in DOCA+ BH4 mice (P<0.05). (6) The expression of PI3K, Akt and p-Akt (Ser473 and Thr308) in DOCA mice were significantly lower than in Sham group (P<0.05). The expression of PI3K, Akt and p-Akt (Ser473) was significantly higher in DOCA+ BH4 group than in DOCA group (P<0.05). p-Akt (Thr308) expression was similar between DOCA + BH4 group and DOCA group (all P>0.05). Conclusion: Our results suggest that BH4 could improve left ventricular diastolic function in hypertensive mice, this effect might be mediated by reducing the oxidative stress in ventricular myocardium through modlating the expression of Akt and PLB phosphorylation.

Deoxycorticosterone acetate is a steroid hormone produced by the adrenal gland that possesses mineralocorticoid activity and acts as a precursor to aldosterone.

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