scholarly journals Antifibrotic Effect of a Novel Selective 11β-HSD2 Inhibitor (WZ51) in a rat Model of Myocardial Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Fei Zhuang ◽  
Qin Ge ◽  
Jiangchang Qian ◽  
Zhe Wang ◽  
Yaoyao Dong ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Myocardial Fibrosis ◽  
Myocardial Injury ◽  
Therapeutic Agent ◽  
Enzyme Inhibitor ◽  
Hydroxysteroid Dehydrogenase ◽  
Underlying Mechanism ◽  
Mineralocorticoid Receptors ◽  
End Stage

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.

scholarly journals Reduced Placental 11β-Hydroxysteroid Dehydrogenase Type 2 mRNA Levels in Human Pregnancies Complicated by Intrauterine Growth Restriction: An Analysis of Possible Mechanisms

2001 ◽  
Vol 86 (10) ◽  
pp. 4979-4983 ◽  
Author(s):  
C. L. McTernan ◽  
N. Draper ◽  
H. Nicholson ◽  
S. M. Chalder ◽  
P. Driver ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Subsequent Development ◽  
Hydroxysteroid Dehydrogenase ◽  
Underlying Mechanism ◽  
Growth Restriction ◽  
Mrna Levels ◽  
Intrauterine Growth ◽  
Apparent Mineralocorticoid Excess

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates cortisol to cortisone. In the placenta 11β-HSD2 activity is thought to protect the fetus from the deleterious effects of maternal glucocorticoids. Patients with apparent mineralocorticoid excess owing to mutations in the 11β-HSD2 gene invariably have reduced birth weight, and we have recently shown reduced placental 11β-HSD2 activity in pregnancies complicated by intrauterine growth restriction. This is reflected in the literature by evidence of hypercortisolemia in the fetal circulation of small babies. In this study we have determined the levels of placental 11β-HSD2 mRNA expression across normal gestation (n = 86 placentae) and in pregnancies complicated by intrauterine growth restriction (n = 19) and evaluated the underlying mechanism for any aberrant 11β-HSD2 mRNA expression in intrauterine growth restriction. 11β-HSD2 mRNA expression increased more than 50-fold across gestation, peaking at term. Placental 11β-HSD2 mRNA levels were significantly decreased in intrauterine growth restriction pregnancies when compared with gestationally matched, appropriately grown placentae [e.g. at termΔ Ct (11β-hydroxysteroid dehydrogenase type 2/18S) 12.8 ± 0.8 (mean ± se) vs. 10.2 ± 0.2, respectively, P < 0.001]. These differences were not attributable to changes in trophoblast mass in intrauterine growth restriction placentae, as assessed by parallel analyses of cytokeratin-8 mRNA expression. No mutations were found in the 11β-HSD2 gene in the intrauterine growth restriction cohort, and imprinting analysis revealed that the 11β-HSD2 gene was not imprinted. Although the underlying cause is unknown, 11β-HSD2 gene expression is reduced in intrauterine growth restriction pregnancies. These data highlight the important role of 11β-HSD2 in regulating fetal growth, a known factor in determining fetal morbidity but also the subsequent development of cardiovascular disease in adulthood.

scholarly journals Increased colonic K+ excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K+ level in a murine model of nephronic reduction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christine Walter ◽  
Chloé Rafael ◽  
Anthony Genna ◽  
Stéphanie Baron ◽  
Gilles Crambert
Keyword(s):  
Enzyme Inhibitor ◽  
Specific Method ◽  
Proof Of Concept ◽  
Cation Exchange Resins ◽  
Severe Hyperkalemia ◽  
Dependent Absorption ◽  
Targeted Inhibition ◽  
Exchange Resins ◽  
End Stage

AbstractHyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.

scholarly journals Inhibition of IMCD 11 beta-hydroxysteroid dehydrogenase type 2 by low pH and acute acid loading.

1997 ◽  
Vol 8 (4) ◽  
pp. 530-534
Author(s):  
P J Nolan ◽  
M A Knepper ◽  
R K Packer
Keyword(s):  
Conversion Rate ◽  
Intact Cell ◽  
Collecting Duct ◽  
Hydroxysteroid Dehydrogenase ◽  
Cell Suspensions ◽  
Mineralocorticoid Receptors ◽  
Medullary Collecting Duct ◽  
Acute Metabolic Acidosis ◽  
Acid Loading

Mineralocorticoid receptors in the inner medullary collecting duct (IMCD) are protected from glucocorticoid binding by an enzyme, 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2). To study the role of 11 beta-HSD2 in acid-base homeostasis, 11 beta-HSD2 activity was measured in rat IMCD-enriched cell suspensions. Homogenates of cell suspensions were incubated in buffers ranging in pH from 6.00 to 8.15 in the presence of 1 microCi of 3H-corticosterone (CS) and 400 microM NAD+. Enzyme activity was expressed as the amount of 3H-CS converted to 3H-11-dehydrocorticosterone (DHCS). IMCD 11 beta-HSD2 activity at pH 6.5 was 49% of activity at pH 7.5; 22.5 versus 11.0 fmol/microgram of protein per h. Experiments also were performed on intact cell suspensions at pH 7.5 and 6.5. There was a 42% inhibition in the IMCD cell suspension conversion rate of 3H-CS to 3H-11-DHCS at pH 6.5; 13.1 versus 7.6 fmol/microgram per h (P < 0.005). In cell suspensions at pH 7.5, 1-day acid loading caused a 26% inhibition in conversion rate, 13.2 versus 9.9 fmol/microgram per h (P < 0.05), when compared with controls. These results suggest that during acute metabolic acidosis, IMCD 11 beta-HSD2 is inhibited and may allow access to the mineralocorticoid receptors by glucocorticoids.

scholarly journals Structural analysis of the 11β-hydroxysteroid dehydrogenase type 2 gene in end-stage renal disease

2000 ◽  
Vol 58 (4) ◽  
pp. 1413-1419 ◽  
Author(s):  
Tanja Zaehner ◽  
Valmai Plueshke ◽  
Brigitte M. Frey ◽  
Felix J. Frey ◽  
Paolo Ferrari
Keyword(s):  
Structural Analysis ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Hydroxysteroid Dehydrogenase ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals Localizations of 11ß‐hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptors in the rat hypothalamus

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Remi Aleaha Wilson ◽  
Lee G. Shelton ◽  
Masudul Haque ◽  
Narine E.J. Wandrey ◽  
Lori L Wilson ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Mineralocorticoid Receptors ◽  
Rat Hypothalamus

scholarly journals 11Beta-hydroxysteroid dehydrogenase, mineralocorticoid receptor, and thiazide-sensitive Na-Cl cotransporter expression by distal tubules.

1998 ◽  
Vol 9 (8) ◽  
pp. 1347-1358
Author(s):  
M Bostanjoglo ◽  
W B Reeves ◽  
R F Reilly ◽  
H Velázquez ◽  
N Robertson ◽  
...  
Keyword(s):  
Mineralocorticoid Receptor ◽  
Collecting Duct ◽  
Hydroxysteroid Dehydrogenase ◽  
Receptor Expression ◽  
Salt Transport ◽  
Metabolic Enzyme ◽  
Thick Ascending Limb ◽  
Mineralocorticoid Receptors ◽  
Connecting Tubule

Mineralocorticoid hormones regulate salt transport along the distal nephron by binding to intracellular receptors and activating gene transcription. Previous experiments showed that systemic aldosterone infusions stimulate thiazide-sensitive Na and Cl transport by distal convoluted tubule (DCT) cells; this effect could have been direct or secondary to systemic hormonal effects. Aldosterone target tissues express both mineralocorticoid receptors and the metabolic enzyme 11beta-hydroxysteroid dehydrogenase type 2. Mineralocorticoid receptors have been localized to the DCT in some experiments, but not in others. Expression of 11beta-hydroxysteroid dehydrogenase type 2 by DCT cells has not been investigated. The present experiments were designed to test the hypothesis that rat DCT cells are targets of aldosterone action. Patterns of mineralocorticoid receptor, 11beta-hydroxysteroid dehydrogenase, thiazide-sensitive Na-Cl cotransporter, and Na/Ca exchanger expression along the distal tubule were examined. A polyclonal antibody was generated to localize the thiazide-sensitive Na-Cl cotransporter. Thiazide-sensitive Na-Cl cotransporter and 11beta-hydroxysteroid dehydrogenase expression were examined using both in situ hybridization and immunocytochemistry; Na/Ca exchanger and mineralocorticoid receptor expression were examined by immunocytochemistry. The results indicate that 11beta-hydroxysteroid dehydrogenase is expressed by DCT cells, as well as connecting tubule cells and principal cells of the collecting duct; expression levels are low near the junction with the thick ascending limb and rise near the transition to the connecting tubule. Mineralocorticoid receptors are expressed by DCT cells, as well as along the thick ascending limb, connecting tubule, and collecting duct. The results indicate that components of the mineralocorticoid receptor system are expressed by DCT cells, suggesting that these cells are targets of aldosterone action.

Sign in / Sign up

Export Citation Format

Share Document