Roles of Bone Morphogenetic Protein-6 in Aldosterone Regulation by Adrenocortical Cells

Published on Aug 1, 2010in Acta Medica Okayama0.642
· DOI :10.18926/AMO/40128
Hiroyuki Otani16
Estimated H-index: 16
(Okayama University),
Fumio Otsuka35
Estimated H-index: 35
(Okayama University)
+ 2 AuthorsHirofumi Makino98
Estimated H-index: 98
(Okayama University)
Sources
Abstract
Aldosterone production occurs in the adrenal cortex, and is regulated primarily by angiotensin II (Ang II), potassium and adrenocorticotropin (ACTH). In the presence of the aldosterone stimulators, steroidogenesis is further governed by local autocrine and/or paracrine factors in the adrenal cortex. We reported the presence of functional bone morphogenetic protein (BMP) system in the adrenal cortex and also demonstrated that BMP-6 increases Ang II-induced aldosterone production, which could be involved in the "aldosterone breakthrough" phenomenon. Aldosterone breakthrough is the phenomenon by which circulating aldosterone concentrations increase above pre-treatment levels after long-term therapy with ACE inhibitors or Ang II type 1 receptor antagonists (ARB). This phenomenon may lead to important clinical consequences since increased aldosterone in a high-salt state facilitates cardiovascular and renal damage in hypertensive patients. We found that long-term ARB treatment reverses the reduction of aldosterone synthesis by adrenocortical cells, thereby causing "cellular aldosterone breakthrough". The availability of BMP-6 in the adrenal cortex may be at least partly involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.
📖 Papers frequently viewed together
27 Citations
20 Citations
229 Citations
References32
Newest
#1Fumio Otsuka (Okayama University)H-Index: 35
Bone morphogenetic proteins (BMPs) were originally identified with regard to their actions to regulate ectopic formation of bone and cartilage and early embryonic development. Subsequently, our research program has investigated a BMP system that exists in the mammalian ovary and plays roles in regulating numerous granulosa cell functions. BMP ligands including BMP-2, -4, -6, -7 and -15 were found to inhibit gondotropin-dependent progesterone synthesis by granulosa cells, which led to the hypothe...
55 CitationsSource
#1Hiroyuki Otani (Okayama University)H-Index: 16
#2Fumio Otsuka (Okayama University)H-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 11 authors...
Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary–gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor a (ERa; ESR1 as listed in MGI Database), ERb (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA express...
19 CitationsSource
#1Hiroyuki Otani (Okayama University)H-Index: 16
#2Fumio Otsuka (Okayama University)H-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 9 authors...
Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, w...
32 CitationsSource
#1Andrew S. Bomback (UNC: University of North Carolina at Chapel Hill)H-Index: 31
#2Philip J. Klemmer (UNC: University of North Carolina at Chapel Hill)H-Index: 17
Bomback and Klemmer have systematically reviewed the literature on aldosterone breakthrough in people treated with angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers. Although the data are not yet supportive of widespread screening of asymptomatic patients, the authors contend that physicians should test for this phenomenon in selected patients and consider initiating treatment with aldosterone antagonists or renin inhibitors.
284 CitationsSource
#1Hiroyuki Otani (Okayama University)H-Index: 16
#2Fumio OtsukaH-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 9 authors...
Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were ne...
59 CitationsSource
#1Yoshio HoritaH-Index: 12
#2Kouichi TauraH-Index: 6
Last. Shigeru Kohno (Nagasaki University)H-Index: 94
view all 5 authors...
SUMMARY: Background: We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). Methods: We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 ± 0.3 g/day) outpatients (aged 41.5 ± 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were tre...
61 CitationsSource
#1Kenichi Inagaki (Okayama University)H-Index: 21
#2Fumio Otsuka (Okayama University)H-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 10 authors...
Aldosterone production is modified by several growth factors that reside in the adrenal. We have recently reported the existence of a bone morphogenetic protein (BMP) system in human adrenocortical cells, in which BMP-6 augments aldosterone synthesis. Here, we investigated functional roles of BMP-6, focusing on the differential regulation of aldosterone synthesis induced by angiotensin (Ang) II and potassium (K). In human adrenocortical H295R cells, BMP-6 augmented Ang II-induced CYP11B2 transcr...
40 CitationsSource
#1John M. C. Connell (Glas.: University of Glasgow)H-Index: 81
#2Eleanor DaviesH-Index: 27
Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety ...
264 CitationsSource
#1Jiro Suzuki (Okayama University)H-Index: 18
#2Fumio Otsuka (Okayama University)H-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 9 authors...
Abstract We uncovered a new regulation of thyrocyte function by bone morphogenetic protein (BMP) under the influence of thyrotropin (TSH) using primary culture of porcine thyrocytes. The BMP type I receptors, ALK-2 (ActRIA), -3 (BMPRIA), and -6 (BMPRIB), were expressed in porcine thyrocytes, while ALK-6 was not detected in human thyroid. Treatment with BMP-2, -4, -6, -7, and TGF-β1 exhibited a dose-dependent suppression of DNA synthesis by porcine thyrocytes. BMP-2, -4, -6, -7, and TGF-β1 suppre...
21 CitationsSource
#1Naveed Ahmad (UMMC: University of Mississippi Medical Center)H-Index: 25
#2Damian G. Romero (University of Mississippi)H-Index: 28
Last. Celso E. Gomez-Sanchez (University of Mississippi)H-Index: 79
view all 4 authors...
Extraadrenal production of aldosterone has been reported in several tissues, including vascular endothelial cells. The implications of local production of aldosterone in certain nonepithelial target tissues in normal and pathological physiology could be very important and merits further investigation. Human vascular endothelial cells have been reported to synthesize aldosterone under the regulation of angiotensin II. However, discrepancies are noted upon close scrutiny, the most important of whi...
44 CitationsSource
Cited By6
Newest
#1Alan Nguyen (UC: University of California)H-Index: 11
#2Michelle A. Scott (Children's Hospital Los Angeles)H-Index: 8
Last. Aaron W. James (UC: University of California)H-Index: 45
view all 4 authors...
Purpose Since the original extraction of bone morphogenetic proteins (BMPs) from bovine bone, research interest and clinical use has increased exponentially. With this, a concomitant analysis of BMP expression in bone tumours has been performed. BMP ligands, receptors, and signaling activity have been observed in diverse benign and malignant bone tumours. However, the reported expression, function, and importance of BMPs in bone tumours, and specifically osteosarcomas, have been far from uniform...
18 CitationsSource
#1Fumio Otsuka (Okayama University)H-Index: 35
������������������������������� ������������������������������������������������ ��������������������������������������� � �����������-����� ������ New biological activities of bone morphogenetic proteins (BMPs in the endocrine system have recently been revealed. The BMP system is composed of approximately 30 ligands and preferential combina‑ tions of type I and type II receptors. The BMP system not only induces bone formation but also plays unique tissue‑specific roles in various organs. For ins...
28 CitationsSource
#1Yoshinori Matsumoto (Okayama University)H-Index: 12
#2Fumio Otsuka (Okayama University)H-Index: 35
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 10 authors...
Abstract Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. We previously reported the presence of a functional BMP system including BMP-6 in human adrenocortical cells. BMP-6 contributes to Ang II-induced aldosterone production by activating Smad signaling, in which endogenous BMP-6 action is negatively controlled by Ang II in vitro . In the present study, we examined the in vivo role of BMP-6 in regulation of aldosterone by neutralizing endogenous BMP-6 in rats treated w...
6 CitationsSource
#1Fumio Otsuka (Okayama University)H-Index: 35
#2Naoko Tsukamoto (Okayama University)H-Index: 13
Last. Hirofumi Makino (Okayama University)H-Index: 98
view all 5 authors...
Abstract The existence of a functional bone morphogenetic protein (BMP) system in the pituitary has been recognized. Recent studies have provided evidence that BMPs elicit differential actions in the regulation of prolactin (PRL) and adrenocorticotropin (ACTH) release in lactotropinoma and corticotropinoma cells, respectively. BMPs play a key role in the modulation of somatostatin receptor (SSTR) sensitivity of lactosomatotrope cells in an autocrine/paracrine manner. In addition, SSTR action enh...
16 CitationsSource
#1Yewei Xing (Georgia Regents University)H-Index: 11
#2William E. Rainey (Georgia Regents University)H-Index: 54
Last. Wendy B. Bollag (Veterans Health Administration)H-Index: 3
view all 6 authors...
Very low-density lipoproteins (VLDL) are a class of large lipoprotein synthesized in the liver. The key function of VLDL, in vivo, is to carry triglyceride from the liver to adipose tissue. As a steroidogenic organ, the adrenal gland mainly uses lipoproteins as sources of cholesterol. Although VLDL receptors have been detected in the human adrenal, the function of VLDL in the adrenal gland remains unknown. Herein, we used primary cultures of human and bovine adrenal cells and the adrenocortical ...
24 CitationsSource
#1Juan F. Santibanez (University of Belgrade)H-Index: 28
#2Miguel Quintanilla (CSIC: Spanish National Research Council)H-Index: 51
Last. Carmelo Bernabeu (CSIC: Spanish National Research Council)H-Index: 70
view all 3 authors...
The TGF-β (transforming growth factor-β) system signals via protein kinase receptors and Smad mediators to regulate a plethora of biological processes, including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. In addition, alterations of specific components of the TGF-β signalling pathway may contribute to a broad range of pathologies such as cancer, cardiovascular pathology, fibrosis and congenital diseases. The knowledge...
270 CitationsSource