Progranulin Deficient Mice Develop Nephrogenic Diabetes Insipidus.

Area of Science:

• Neuroscience
• Nephrology
• Genetics

Background:

• Loss-of-function mutations in progranulin are linked to frontotemporal dementia.
• Progranulin-deficient mice serve as a model for this disease, though typically showing mild cognitive decline and normal lifespan.
• Aging in these mice reveals previously undocumented physiological changes.

Purpose of the Study:

• To investigate the physiological consequences of aging in progranulin-deficient mice.
• To characterize the observed polydipsia and polyuria in these aging mice.
• To determine the underlying mechanisms of the observed water balance abnormalities.

Main Methods:

• Observation of polydipsia and polyuria in aging progranulin-deficient mice.
• Analysis of urine osmolality, creatinine clearance, urine urea, and albumin.
• Kidney morphology and histology examination.
• Measurement of plasma vasopressin levels and aquaporin-2 immunofluorescence in kidney tubules.
• Assessment of renal and hypothalamic vasopressin and hypothalamic astrogliosis.

Main Results:

• Aging progranulin-deficient mice exhibit progressive polydipsia and polyuria starting at middle age.
• These mice show decreased urine osmolality despite water restriction, indicating a concentrating defect without osmotic diuresis or overt renal disease.
• Kidney enlargement, medullary inflammation, and widened tubules were observed, alongside diminished aquaporin-2 expression in collecting tubules.
• Elevated plasma vasopressin levels suggest collecting tubule unresponsiveness to vasopressin.

Conclusions:

• Progranulin deficiency in aging mice leads to nephrogenic diabetes insipidus.
• The findings suggest a defect in the kidney's concentrating ability due to vasopressin unresponsiveness.
• Observed polydipsia in human frontotemporal dementia patients might indicate a similar renal concentrating defect.