Masters Theses

Date of Award

12-1996

Degree Type

Thesis

Degree Name

Master of Science

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

Virginia L. Godfrey

Committee Members

J. Erby Wilkinson, Steve Kennel

Abstract

At The Oak Ridge National Laboratory, a syndrome of excessive urination (polyuria) and excessive water intake (polydipsia) was noted in older mice of the CFW, CFCW, and IMNURd strains. Random measurements of urine specific gravities showed that affected mice were excreting a very dilute urine. Preliminary experiments have measured urine specific gravities ranging from extremely dilute concentration (1.003) in older mice to normal concentration (greater than or equal to 1.040) in younger mice. In water deprivation tests, affected mice lost up to 5% of their body weight within 30 minutes without concentrating their urine. Affected mice were unresponsive to administration of exogenous vasopressin (ADH).

The purpose of this inquiry was to study the pathophysiology of these three strains in order to characterize the abnormality exhibited by these mice and to evaluate the mice as potential models for disease. Furthermore, we wished to make a comparison of this defect with other strains of mice which have been documented to have polyuria and polydipsia.

Experiments conducted in this study include: measurement of urine specific gravity to categorize the animal as normal or mutant, measurement of serum and urine osmolalities to verify specific gravity data, measurement of water intake and urine output, urinalyses to investigate various causes of polyuria and polydipsia, serum chemistry assays to check for renal failure, in vivoresponsiveness to ADH, measurement of serum and urine electrolytes to indicate fractional excretion of ions, and histological studies to detect morphologic lesions that might cause polyuria and polydipsia.

Measurement of urine specific gravity revealed that the specific gravity declined as age increased. All three strains had lower than normal urine osmolalities in aged mice and higher than normal serum osmolalities. Water intakes were 1 1/2 to 4 times normal volumes, whereas urine output was 3 to 10 times more than normal outputs. Urinalyses measuring glucose, ketones, urobilogen, protein, pH, blood, and bilirubin levels in the urinewere normal for most animals and serum chemistry analyses showed that blood urea nitrogen and total serum protein were within normal limits. Serum levels of potassium (K+) were normal, but chloride (CI-) levels were slightly elevated. Serum sodium (Na+) levels increased over normal levels at approximately 11 months of age. Fractional excretion of sodium was higher than normal for all three strains; only CFCW had higher than normal levels of potassium fractional excretion. Chloride fractional excretion in CFW and CFCW mice was also higher than normal. Necropsy shows severely atonic bladders in most animals, moderate to severe hydronephrosis of the renal pelvis in 16 of 26 animals necropsied (62%), and renal tubule dilation in 21 of 26 animals necropsied (81%).

From these data, we were able to discount all the common and uncommon causes of polyuria and polydipsia with the exception of diabetes insipidus. Furthermore, we were able to characterize the diabetes insipidus as nephrogenic diabetes insipidus. Based upon these conclusions, we believe these strains to be good models of nephrogenic diabetes insipidus in humans.

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