RGD Reference Report - Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model. - Rat Genome Database

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Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model.

Authors: Mullins, Linda J  Kenyon, Christopher J  Bailey, Matthew A  Conway, Bryan R  Diaz, Mary E  Mullins, John J 
Citation: Mullins LJ, etal., Hypertension. 2015 Sep;66(3):667-73. doi: 10.1161/HYPERTENSIONAHA.115.05262. Epub 2015 Jun 15.
RGD ID: 13800514
Pubmed: PMID:26077568   (View Abstract at PubMed)
PMCID: PMC4847935   (View Article at PubMed Central)
DOI: DOI:10.1161/HYPERTENSIONAHA.115.05262   (Journal Full-text)

Obesity and hypertension are 2 major health issues of the 21st century. The syndrome of apparent mineralocorticoid excess is caused by deficiency of 11ß-hydroxysteroid dehydrogenase type 2 (Hsd11b2), which normally inactivates glucocorticoids, rendering the mineralocorticoid receptor aldosterone-specific. The metabolic consequences of Hsd11b2 knockout in the rat are investigated in parallel with electrolyte homeostasis. Hsd11b2 was knocked out, by pronuclear microinjection of targeted zinc-finger nuclease mRNAs, and 1 line was characterized for its response to renal and metabolic challenges. Plasma 11-dehydrocorticosterone was below detection thresholds, and Hsd11b2 protein was undetected by Western blot, indicating complete ablation. Homozygotes were 13% smaller than wild-type littermates, and were polydipsic and polyuric. Their kidneys, adrenals, and hearts were significantly enlarged, but mesenteric fat pads and liver were significantly smaller. On a 0.3% Na diet, mean arterial blood pressure was ˜65 mm Hg higher than controls but only 25 mm Hg higher on a 0.03% Na(+) diet. Urinary Na/K ratio of homozygotes was similar to controls on 0.3% Na(+) diet but urinary albumin and calcium were elevated. Corticosterone and aldosterone levels showed normal circadian variation on both a 0.3% and 0.03% Na(+) diet, but plasma renin was suppressed in homozygotes on both diets. Plasma glucose responses to an oral glucose challenge were reduced despite low circulating insulin, indicating much greater sensitivity to insulin in homozygotes. The rat model reveals mechanisms linking electrolyte homeostasis and metabolic control through the restriction of Hsd11b1 substrate availability.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344-Hsd11b2em1Jmul-/-Rathypertension  IMP  RGD 
HSD11B2Humanhypertension  ISOHsd11b2 (Rattus norvegicus) RGD 
Hsd11b2Rathypertension  IMP  RGD 
Hsd11b2Mousehypertension  ISOHsd11b2 (Rattus norvegicus) RGD 
Hsd11b2em1JmulRathypertension  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F344-Hsd11b2em1Jmul-/-Ratabnormal adrenal gland zona glomerulosa morphology  IMP  RGD 
Hsd11b2Ratabnormal adrenal gland zona glomerulosa morphology  IMP  RGD 
Hsd11b2em1JmulRatabnormal adrenal gland zona glomerulosa morphology  IMP  RGD 
F344-Hsd11b2em1Jmul-/-Ratabnormal adrenal gland zona reticularis morphology  IMP  RGD 
Hsd11b2Ratabnormal adrenal gland zona reticularis morphology  IMP  RGD 
Hsd11b2em1JmulRatabnormal adrenal gland zona reticularis morphology  IMP  RGD 
F344-Hsd11b2em1Jmul-/-Ratabnormal adrenal medulla morphology  IMP  RGD 
Hsd11b2Ratabnormal adrenal medulla morphology  IMP  RGD 
Hsd11b2em1JmulRatabnormal adrenal medulla morphology  IMP  RGD 
F344-Hsd11b2em1Jmul-/-Ratabnormal distal convoluted tubule morphology  IMP  RGD 
Hsd11b2Ratabnormal distal convoluted tubule morphology  IMP  RGD 
Hsd11b2em1JmulRatabnormal distal convoluted tubule morphology  IMP  RGD 
F344-Hsd11b2em1Jmul-/-Ratdecreased body weight  IMP compared to wild typeRGD 
Hsd11b2Ratdecreased body weight  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatdecreased body weight  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratdecreased circulating renin level  IMP compared to wild typeRGD 
Hsd11b2Ratdecreased circulating renin level  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatdecreased circulating renin level  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratdecreased fat cell size  IMP compared to wild typeRGD 
Hsd11b2Ratdecreased fat cell size  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatdecreased fat cell size  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratdecreased liver weight  IMP compared to wild typeRGD 
Hsd11b2Ratdecreased liver weight  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatdecreased liver weight  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratdecreased mesenteric fat pad weight  IMP compared to wild typeRGD 
Hsd11b2Ratdecreased mesenteric fat pad weight  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatdecreased mesenteric fat pad weight  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratenlarged adrenal glands  IMP compared to wild typeRGD 
Hsd11b2Ratenlarged adrenal glands  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatenlarged adrenal glands  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratincreased heart weight  IMP compared to wild typeRGD 
Hsd11b2Ratincreased heart weight  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatincreased heart weight  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratincreased insulin sensitivity  IMP compared to wild typeRGD 
Hsd11b2Ratincreased insulin sensitivity  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatincreased insulin sensitivity  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratincreased kidney weight  IMP compared to wild typeRGD 
Hsd11b2Ratincreased kidney weight  IMP compared to wild typeRGD 
Hsd11b2em1JmulRatincreased kidney weight  IMP compared to wild typeRGD 
F344-Hsd11b2em1Jmul-/-Ratsalt-sensitive hypertension  IMP  RGD 
Hsd11b2Ratsalt-sensitive hypertension  IMP  RGD 
Hsd11b2em1JmulRatsalt-sensitive hypertension  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hsd11b2  (hydroxysteroid 11-beta dehydrogenase 2)
Hsd11b2em1Jmul  (hydroxysteroid 11-beta dehydrogenase 2; ZFN induced mutant1, Jmul)

Genes (Mus musculus)
Hsd11b2  (hydroxysteroid 11-beta dehydrogenase 2)

Genes (Homo sapiens)
HSD11B2  (hydroxysteroid 11-beta dehydrogenase 2)

Strains
F344-Hsd11b2em1Jmul-/-  (F344-Hsd11b2em1Jmul-/Hsd11b2em1Jmul-)


Additional Information