Progranulin Deficient Mice Develop Nephrogenic Diabetes Insipidus

Abstract

Loss-of-function mutations of progranulin are associated with frontotemporal dementia in humans, and its deficiency in mice is a model for this disease but with normal life expectancy and mild cognitive decline on aging. The present study shows that aging progranulin deficient mice develop progressive polydipsia and polyuria under standard housing conditions starting at middle age (6-9 months). They showed high water licking behavior and doubling of the normal daily drinking volume, associated with increased daily urine output and a decrease of urine osmolality, all maintained during water restriction. Creatinine clearance, urine urea, urine albumin and glucose were normal. Hence, there were no signs of osmotic diuresis or overt renal disease, other than a concentrating defect. In line, the kidney morphology and histology revealed a 50% increase of the kidney weight, kidney enlargement, mild infiltrations of the medulla with pro-inflammatory cells, widening of tubules but no overt signs of a glomerular or tubular pathology. Plasma vasopressin levels were on average about 3-fold higher than normal levels, suggesting that the water loss resulted from unresponsiveness of the collecting tubules towards vasopressin, and indeed aquaporin-2 immunofluorescence in collecting tubules was diminished, whereas renal and hypothalamic vasopressin were increased, the latter in spite of substantial astrogliosis in the hypothalamus. The data suggest that progranulin deficiency causes nephrogenic diabetes insipidus in mice during aging. Possibly, polydipsia in affected patients - eventually interpreted as psychogenic polydipsia - may point to a similar concentrating defect.

PGRN acts as a novel regulator of mitochondrial homeostasis by facilitating mitophagy and mitochondrial biogenesis to prevent podocyte injury in diabetic nephropathy

“…We further found that under the normal conditions, PGRN deficiency in mice had no effects on renal function including the podocyte structure and function, which was consistent with previous studies showing that PGRN knockout mice display normal life expectancy with behavioral deficits and progressive neuropathology but few other recorded phenotypes 26 . Although a recent study has shown that PGRN deficiency mice develop progressive polydipsia and polyuria due to increased drinking behavior and urinary concentrating defect during aging (starting at 6 months), the renal function of aged Grn −/− mice were in the normal range and there were no overt signs of a glomerular or tubular pathology 27 . In this study, we found that there was no significant difference in mitochondrial morphology of podocytes, kidney morphology and urinary albumin excretion between Grn −/− mice (<5 months) and age-matched WT mice under normal condition.…”

Reduced exploratory behavior in neuronal nucleoredoxin knockout mice

“…The IntelliCage (NewBehavior AG, Zurich, Switzerland) [ 30 , 51 , [74] , [75] , [76] ] consists of four operant corners, each with two water bottles, sensors, light-emitting-diodes (LEDs) and doors that control the access to the water bottles. The system fits into a large cage (20 × 55 × 38 cm, Tecniplast, 2000P) and allows housing of 16 mice per cage.…”

Increased Fat Taste Preference in Progranulin-Deficient Mice

“…The IntelliCage (NewBehavior AG, Zurich, Switzerland) [25,[63][64][65][66] consisted of four operant corners, each with two water bottles, sensors, light-emitting-diodes (LEDs) and doors that controlled the access to the water bottles. The system fit into a large cage (20 cm × 55 cm × 38 cm, Tecniplast, Germany, 2000P) and housed 16 mice per cage.…”