The effects of different rearing conditions on sexual maturation and maternal care in heterozygous mineralocorticoid receptor knockout mice

Mineralocorticoid receptor (MR)-deficient mice were generated by gene targeting. These animals had a normal prenatal development. During the first week of life, MR-deficient (−/−) mice developed symptoms of pseudohypoaldosteronism. They finally lost weight and eventually died at around day 10 after birth from dehydration by renal sodium and water loss. At day 8, −/− mice showed hyperkalemia, hyponatremia, and a strong increase in renin, angiotensin II, and aldosterone plasma concentrations. Methods were established to measure renal clearance and colonic transepithelial Na+ reabsorption in 8-day-old mice in vivo. The fractional renal Na+ excretion was elevated >8-fold. The glomerular filtration rate in −/− mice was not different from controls. The effect of amiloride on renal Na+ excretion and colonic transepithelial voltage reflects the function of amiloide-sensitive epithelial Na+ channels (ENaC). In −/− mice, it was reduced to 24% in the kidney and to 16% in the colon. There was, however, still significant residual ENaC-mediated Na+ reabsorption in both epithelia. RNase protection analysis of the subunits of ENaC and (Na++ K+)-ATPase did not reveal a decrease in −/− mice. The present data indicate that MR-deficient neonates die because they are not able to compensate renal Na+ loss. Regulation of Na+ reabsorption via MR is not achieved by transcriptional control of ENaC and (Na+ + K+)-ATPase in RNA abundance but by transcriptional control of other as yet unidentified genes. MR knockout mice will be a suitable tool for the search of these genes.

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Kiss1 −/− Mice Exhibit More Variable Hypogonadism than Gpr54−/− Mice

Endocrinology ◽

10.1210/en.2007-0078 ◽

2007 ◽

Vol 148 (10) ◽

pp. 4927-4936 ◽

Cited By ~ 318

Author(s):

Risto Lapatto ◽

J. Carl Pallais ◽

Dongsheng Zhang ◽

Yee-Ming Chan ◽

Amy Mahan ◽

...

Keyword(s):

Sexual Maturation ◽

Knockout Mice ◽

Genetic Background ◽

Phenotypic Variability ◽

Hypogonadotropic Hypogonadism ◽

Vaginal Opening ◽

Wild Type ◽

Males And Females ◽

G Protein Coupled ◽

Estrous Cycling

The G protein-coupled receptor Gpr54 and its ligand metastin (derived from the Kiss1 gene product kisspeptin) are key gatekeepers of sexual maturation. Gpr54 knockout mice demonstrate hypogonadotropic hypogonadism, but until recently, the phenotype of Kiss1 knockout mice was unknown. This report describes the reproductive phenotypes of mice carrying targeted deletions of Kiss1 or Gpr54 on the same genetic background. Both Kiss1 and Gpr54 knockout mice are viable but infertile and have abnormal sexual maturation; the majority of males lack preputial separation, and females have delayed vaginal opening and absence of estrous cycling. Kiss1 and Gpr54 knockout males have significantly smaller testes compared with controls. Gpr54 knockout females have smaller ovaries and uteri than wild-type females. However, Kiss1 knockout females demonstrate two distinct phenotypes: half have markedly reduced gonadal weights similar to those of Gpr54 knockout mice, whereas half exhibit persistent vaginal cornification and have gonadal weights comparable with those of wild-type females. FSH levels in both Kiss1 and Gpr54 knockout males and females are significantly lower than in controls. When injected with mouse metastin 43–52, a Gpr54 agonist, Gpr54 knockout mice fail to increase gonadotropins, whereas Kiss1 knockout mice respond with increased gonadotropin levels. In summary, both Kiss1 and Gpr54 knockout mice have abnormal sexual maturation consistent with hypogonadotropic hypogonadism, although Kiss1 knockout mice appear to be less severely affected than their receptor counterparts. Kiss1 knockout females demonstrate a bimodal phenotypic variability, with some animals having higher gonadal weight, larger vaginal opening, and persistent vaginal cornification.

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Living in a dangerous world decreases maternal care: A study in serotonin transporter knockout mice

Hormones and Behavior ◽

10.1016/j.yhbeh.2011.07.006 ◽

2011 ◽

Vol 60 (4) ◽

pp. 397-407 ◽

Cited By ~ 24

Author(s):

Rebecca S. Heiming ◽

Carina Bodden ◽

Friederike Jansen ◽

Lars Lewejohann ◽

Sylvia Kaiser ◽

...

Keyword(s):

Serotonin Transporter ◽

Knockout Mice ◽

Maternal Care

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Aldosterone Regulates Pendrin and Epithelial Sodium Channel Activity through Intercalated Cell Mineralocorticoid Receptor–Dependent and –Independent Mechanisms over a Wide Range in Serum Potassium

Journal of the American Society of Nephrology ◽

10.1681/asn.2019050551 ◽

2020 ◽

Vol 31 (3) ◽

pp. 483-499 ◽

Cited By ~ 4

Author(s):

Truyen D. Pham ◽

Jill W. Verlander ◽

Yanhua Wang ◽

Cesar A. Romero ◽

Qiang Yue ◽

...

Keyword(s):

Sodium Channel ◽

Serum Potassium ◽

Knockout Mice ◽

Subcellular Distribution ◽

Mineralocorticoid Receptor ◽

Epithelial Sodium Channel ◽

Principal Cell ◽

Channel Activity ◽

Intercalated Cell ◽

Chloride Absorption

BackgroundAldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger pendrin is unclear, as are potassium’s role in this response and the receptor’s effect on intercalated and principal cell function in the cortical collecting duct (CCD).MethodsWe measured CCD chloride absorption, transepithelial voltage, epithelial sodium channel activity, and pendrin abundance and subcellular distribution in wild-type and intercalated cell–specific mineralocorticoid receptor knockout mice. To determine if the receptor directly regulates pendrin, as well as the effect of serum aldosterone and potassium on this response, we measured pendrin label intensity and subcellular distribution in wild-type mice, knockout mice, and receptor-positive and receptor-negative intercalated cells from the same knockout mice.ResultsAblation of the intercalated cell mineralocorticoid receptor in CCDs from aldosterone-treated mice reduced chloride absorption and epithelial sodium channel activity, despite principal cell mineralocorticoid receptor expression in the knockout mice. With high circulating aldosterone, intercalated cell mineralocorticoid receptor gene ablation directly reduced pendrin’s relative abundance in the apical membrane region and pendrin abundance per cell whether serum potassium was high or low. Intercalated cell mineralocorticoid receptor ablation blunted, but did not eliminate, aldosterone’s effect on pendrin total and apical abundance and subcellular distribution.ConclusionsWith high circulating aldosterone, intercalated cell mineralocorticoid receptor ablation reduces chloride absorption in the CCD and indirectly reduces principal cell epithelial sodium channel abundance and function. This receptor directly regulates pendrin’s total abundance and its relative abundance in the apical membrane region over a wide range in serum potassium concentration. Aldosterone regulates pendrin through mechanisms both dependent and independent of the IC MR receptor.

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Mutations along the pituitary–gonadal axis affecting sexual maturation: Novel information from transgenic and knockout mice

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2006.04.015 ◽

2006 ◽

Vol 254-255 ◽

pp. 84-90 ◽

Cited By ~ 34

Author(s):

Ilpo Huhtaniemi

Keyword(s):

Sexual Maturation ◽

Knockout Mice

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Induction of the epithelial Na+ channel via glucocorticoids in mineralocorticoid receptor knockout mice

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s004240100694 ◽

2001 ◽

Vol 443 (2) ◽

pp. 297-305 ◽

Cited By ~ 38

Author(s):

A. Schulz-Baldes ◽

S. Berger ◽

F. Grahammer ◽

R. Warth ◽

I. Goldschmidt ◽

...

Keyword(s):

Knockout Mice ◽

Mineralocorticoid Receptor ◽

Na Channel ◽

Epithelial Na Channel

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Rapid Nongenomic Effects of Aldosterone in Mineralocorticoid-Receptor-Knockout Mice

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1999.1771 ◽

1999 ◽

Vol 266 (1) ◽

pp. 257-261 ◽

Cited By ~ 105

Author(s):

Karin Haseroth ◽

Dirk Gerdes ◽

Stefan Berger ◽

Martin Feuring ◽

Andreas Günther ◽

...

Keyword(s):

Knockout Mice ◽

Mineralocorticoid Receptor ◽

Nongenomic Effects

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Two Mineralocorticoid Receptor–Mediated Mechanisms of Pendrin Activation in Distal Nephrons

Journal of the American Society of Nephrology ◽

10.1681/asn.2019080804 ◽

2020 ◽

Vol 31 (4) ◽

pp. 748-764 ◽

Cited By ~ 1

Author(s):

Nobuhiro Ayuzawa ◽

Mitsuhiro Nishimoto ◽

Kohei Ueda ◽

Daigoro Hirohama ◽

Wakako Kawarazaki ◽

...

Keyword(s):

Sodium Chloride ◽

Angiotensin Ii ◽

Knockout Mice ◽

Mineralocorticoid Receptor ◽

Receptor Activation ◽

Intercalated Cells ◽

Renin Angiotensin Aldosterone System ◽

Salt Diet ◽

Principal Cells ◽

Salt Sensitive Hypertension

BackgroundRegulation of sodium chloride transport in the aldosterone-sensitive distal nephron is essential for fluid homeostasis and BP control. The chloride-bicarbonate exchanger pendrin in β-intercalated cells, along with sodium chloride cotransporter (NCC) in distal convoluted tubules, complementarily regulate sodium chloride handling, which is controlled by the renin-angiotensin-aldosterone system.MethodsUsing mice with mineralocorticoid receptor deletion in intercalated cells, we examined the mechanism and roles of pendrin upregulation via mineralocorticoid receptor in two different models of renin-angiotensin-aldosterone system activation. We also used aldosterone-treated NCC knockout mice to examine the role of pendrin regulation in salt-sensitive hypertension.ResultsDeletion of mineralocorticoid receptor in intercalated cells suppressed the increase in renal pendrin expression induced by either exogenous angiotensin II infusion or endogenous angiotensin II upregulation via salt restriction. When fed a low-salt diet, intercalated cell–specific mineralocorticoid receptor knockout mice with suppression of pendrin upregulation showed BP reduction that was attenuated by compensatory activation of NCC. In contrast, upregulation of pendrin induced by aldosterone excess combined with a high-salt diet was scarcely affected by deletion of mineralocorticoid receptor in intercalated cells, but depended instead on hypokalemic alkalosis through the activated mineralocorticoid receptor–epithelial sodium channel cascade in principal cells. In aldosterone-treated NCC knockout mice showing upregulation of pendrin, potassium supplementation corrected alkalosis and inhibited the pendrin upregulation, thereby lowering BP.ConclusionsIn conjunction with NCC, the two pathways of pendrin upregulation, induced by angiotensin II through mineralocorticoid receptor activation in intercalated cells and by alkalosis through mineralocorticoid receptor activation in principal cells, play important roles in fluid homeostasis during salt depletion and salt-sensitive hypertension mediated by aldosterone excess.

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