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Aging and disease    2018, Vol. 9 Issue (5) : 817-830     DOI: 10.14336/AD.2017.1127
Orginal Article |
Progranulin Deficient Mice Develop Nephrogenic Diabetes Insipidus
Stefanie Hardt1, Lucie Valek1,  Jinyang Zeng-Brouwers2,  Annett Wilken-Schmitz1, Liliana Schaefer2,  Irmgard Tegeder1,*
1Clinical Pharmacology, Goethe-University Hospital Frankfurt am Main, Germany
2General Pharmacology and Toxicology, Goethe-University Hospital Frankfurt am Main, Germany
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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.

Keywords Progranulin      aging      polyuria      polydipsia      knockout mice      hypothalamus      vasopressin     
Corresponding Authors: Irmgard Tegeder   
About author: These authors contributed equally to this work.
Issue Date: 04 October 2017
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Hardt Stefanie
Valek Lucie
Zeng-Brouwers Jinyang
Wilken-Schmitz Annett
Schaefer Liliana
Tegeder Irmgard
Cite this article:   
Hardt Stefanie,Valek Lucie,Zeng-Brouwers Jinyang, et al. Progranulin Deficient Mice Develop Nephrogenic Diabetes Insipidus[J]. Aging and disease, 2018, 9(5): 817-830.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1127     OR     http://www.aginganddisease.org/EN/Y2018/V9/I5/817
Figure 1.  Body weight, drinking and feeding behavior of progranulin deficient (Grn<sup>-/-</sup>) and control mice (Grn<sup>+/+</sup>)

A) Scatter plots showing the body weight of young and aged male and female Grn-/- and Grn+/+ mice. B) Organ weights of aged Grn-/- and Grn+/+ mice. C) Number of lickings within 24h in the IntelliCage during free-drinking and restricted-drinking experiments. During ’free-drinking’, access to the water bottles was allowed for 24h on nosepoking at the doors. During ’restricted-drinking’, access to the water bottles was mostly denied except for 2x2h per day (11-12 am and 4-5 pm). D) Scatter plots showing the 24h drinking volume of aged Grn-/- and Grn+/+ mice during free drinking and water restriction for 2x12h with one-hour free drinking in between. E) Scatter plots showing the weight of food and water consumed within 24h in sex-matched young and aged Grn-/- and Grn+/+ mice in the Phenomaster cage. F) Phenomaster analysis of drinking and feeding behavior of old Grn-/- and Grn+/+ mice during presentation of tap water or sweet water with 20% sucrose (mean ± SD). The data show the food weight and drinking volume consumed within 24h. For all subpanels each scatter represents one mouse, the line is the mean and the whisker show the standard deviation (SD). Asterisks indicate statistically significant differences between genotypes (unpaired, 2-tailed Student’s t-test for each gender, organ, drinking or feeding. * P< 0.05, ** P<0.01, *** P<0.001, **** P<0.0001).

Figure 2.  Renal and metabolic functions of progranulin deficient (Grn<sup>-/-</sup>) and control mice (Grn<sup>+/+</sup>)

A) Scatter plots showing the 24h urine volume, urine osmolality and urine specific gravity of aged Grn-/- and Grn+/+ mice (12-16 months old). B) Concentration of glucose in 24h-urine and plasma of aged Grn-/- and Grn+/+ mice. C) Creatinine concentrations in 24h-urine and plasma, and creatinine clearance of aged Grn-/- and Grn+/+ mice. D) Concentrations of urea and albumin in 24h-urine of aged Grn-/- and Grn+/+ mice. E) Concentrations of arginine vasopressin (AVP, antidiuretic hormone) in plasma and in crude tissue extracts of the hypothalamus of aged Grn-/- and Grn+/+ mice and immunofluorescence analysis of AVP in the kidney (bottom, scale bar 50 µm). F, G) Plasma concentrations of ghrelin and agouti related protein (Agrp) of aged Grn-/- and Grn+/+ mice. For all subpanels each scatter represents one mouse, sexes were matched between groups, the line is the mean and the whisker show the standard deviation (SD). Asterisks indicate statistically significant differences between genotypes (unpaired, 2-tailed Student’s t-test. * P< 0.05, ** P<0.01, *** P<0.001).

Figure 3.  Histomorphology of the kidney of aged progranulin deficient (Grn<sup>-/-</sup>) and control mice (Grn<sup>+/+</sup>)

A) Immunostaining of myeloid-derived F48/80-positive immune cells (brown), with hematoxylin counterstaining of nuclei (blue). Immune cells were counted per field of view and averaged (10 fields per mouse of 3 mice per group). Numbers differed significantly between genotypes (unpaired, 2-tailed Student’s t-test). Scale bars 50 µm. B) Periodic acid-Schiff (PAS) staining of polysaccharides and mucous substances. Histomorphometric scores did not differ between genotypes, except for a higher number of immune cells in Grn-/- mice. Scale bars 50 µm. C, D) Concentrations of C-reactive protein (CRP) and zinc in plasma of aged Grn-/- and Grn+/+ mice. Asterisks indicate statistically significant differences between genotypes (unpaired, 2-tailed Student’s t-test, **** P<0.0001).

Figure 4.  Immunofluorescence analysis of aquaporin 1, 2 and 4 (AQP1, AQP2, AQP4) in the kidney of aged progranulin deficient (Grn<sup>-/-</sup>) and control mice (Grn<sup>+/+</sup>)

A) Examples of AQP2 immunofluorescence at low (upper panels) and high magnifications (bottom panels and insert). Scale bars as indicated in the figure. The bottom panel also shows high AQP1 and AQP4 at high magnification, which did not differ between genotypes. B) Quantification of AQP2 positive particles using stitched full sections of the kidney of 4 mice per group. Each scatter is a section. Analysis of the tubule lumen as assessed by measuring the lumen area in 4 sections of 4 mice per group. Each scatter is one AQP2 positive collecting duct. The images suggest reduced AQP2 expression and widening of AQP2+ collecting ducts. Asterisks indicate significant differences between genotypes, unpaired 2-tailed Student’s t-test *P<0.05, ***P<0.001).

Figure 5.  Immunofluorescence analysis of arginine vasopressin (AVP), glial fibrillary acidic protein (GFAP) of astrocytes and DAPI counterstain of nuclei in the hypothalamus of aged progranulin deficient (Grn<sup>-/-</sup>) and control mice (Grn<sup>+/+</sup>)

The Gensat images in the right give an overview of the localization of the paraventricular nucleus (PVN) and the nucleus supraopticus (SON), which are the major sites for vasopressin producing neurons. The upper panels show AVP, GFAP and DAPI in the PVN as overview and zoom-in images, and the lower panels show the SON. AVP immunofluorescence was more intense in Grn-/- and AVP positive neurons appear to be enlarged. GFAP staining reveals astrogliosis in Grn-/-. Scale bars 300 µm for overviews and 100 µm for zoom-in images.

GenotypeWksml/24hgUrine (mmol/l)Serum (mmol/l)



AgeDrinkBWCreaCaClKMgNaPGlcUreaCaClKMgNaPmosmol/kg
Grn-/-42.37.525.51.7684.150.6105.73.43711.713.1102.31114.30.91462.0315.1
Grn-/-42.39.026.61.8003.455.196.23.54212.514.59.62.31114.91.11452.0314.1
Grn-/-42.33.325.21.7742.629.174.90.83110.112.79.72.31124.91.01491.8320.4
Grn-/-42.33.825.41.2983.241.985.43.04012.414.08.92.31083.81.01432.0308.9
Grn-/-42.32.726.01.5445.155.987.83.3612.013.09.22.41104.11.11472.3316.2
Grn-/-46.48.724.80.4130.417.228.20.6169.216.37.32.31124.10.91462.0315.6
Grn-/-51.16.027.21.0912.145.274.60.34110.915.67.22.41144.00.91492.0320.8

Grn+/+50.72.624.03.4006.338.9154.23.43814.414.97.12.41113.71.01472.0316.0
Grn+/+48.61.123.72.8313.237.2120.23.44514.713.110.22.41124.21.01502.0323.3
Grn+/+48.61.224.21.4754.357.8114.93.45613.88.812.12.41125.20.91481.4316.9
Grn+/+44.70.824.01.5815.640.498.03.4476.111.46.82.31124.30.91491.6316.2
Grn+/+43.60.323.32.2882.648.2215.93.5359.913.57.42.41094.30.91461.8312.9
Grn+/+43.74.724.11.7043.539.688.13.32813.3-8.82.41123.91.01482.0-
Means
Grn-/-44.15.925.81.3843.042.178.92.138.39.814.28.82.3111.14.31.0146.42.0315.9
Grn+/+46.61.823.92.2134.243.7131.93.441.512.012.38.72.4111.34.31.0148.01.8317.1

Grn-/-SD3.52.60.80.5061.514.325.01.513.53.61.41.10.01.90.40.12.10.14.0
Grn+/+SD3.01.60.30.7751.47.947.00.19.93.42.32.10.01.20.50.11.40.33.8
t-test P0.1960.0070.00030.0410.1540.8200.0250.0570.6400.2900.1180.9070.0530.8350.9020.4160.1550.0830.6178
Table 1  Serum and urine electrolytes in progranulin knockout (Grn-/-) and wildtype (Grn+/+) female mice.
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