Disease relevance of Nphp3

• Genetic mapping of the polycystic kidney gene, pcy, on mouse chromosome 9 [1].
• DBA/2FG-pcy/pcy mice of either sex developed slowly progressive renal enlargement and azotemia [2].
• The objective of these studies was to examine the effects of early dietary protein restriction on disease progression and survival in the DBA/2FG-pcy (pcy) mouse model of polycystic kidney disease [3].
• These studies illustrate that renal cAMP production and excretion increase in concert with the cystic enlargement of the kidneys in DBA/2FG-pcy/pcy mice and identify a lipid cAMP agonist in murine renal cystic kidney disease [4].
• In adult pcy mice, low- compared with high-fat diets lowered kidney weights (2.4 +/- 0.2 vs. 3.1 +/- 0.2 g/100 g body weight, P = 0.006) and serum urea nitrogen (SUN) (9.6 +/- 0.6 vs. 11.9 +/- 0.6 mmol/L, P = 0.009), whereas in young pcy mice it reduced renal fibrosis volumes (0.44 +/- 0.04 vs. 0.62 +/- 0.04 mL/kg body weight, P < 0.0001) [5].

Psychiatry related information on Nphp3

• Our results suggest that phenotypic expression of the pcy gene in the mouse depends on genetic background, and that variations in the severity of human polycystic kidney disease may be explained, at least in part, by individual differences in genetic background [6].

High impact information on Nphp3

• We show that the mouse ortholog Nphp3 is expressed in the node, kidney tubules, retina, respiratory epithelium, liver, biliary tract and neural tissues [7].
• In addition, we show that a homozygous missense mutation in Nphp3 is probably responsible for the polycystic kidney disease (pcy) mouse phenotype [7].
• Genetic identification of two major modifier loci of polycystic kidney disease progression in pcy mice [8].
• We find that Ke 6 gene expression is down-regulated in pcy mice which is a murine model of polycystic kidney disease (PKD) [9].
• Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium [10].

Chemical compound and disease context of Nphp3

• The effects of feeding a soy protein isolate or genistein, an isoflavonoid present in soy protein, on cyst development were examined in the DBA/2FG-pcy (pcy) mouse, an accepted animal model of polycystic kidney disease, before the appearance of clinical symptoms [11].

Biological context of Nphp3

• One and eight recombinations were detected between D9Mit24 and pcy and between D9Mit16 and pcy, respectively [1].
• Restriction fragment length polymorphism analysis of 70 of the 222 backcross progeny showed that pcy, dilute coat color (d), and cholecystokinin (Cck) were located in the order d--pcy--Cck from the centromere [1].
• Through cloning of the NPH3 critical region and mapping of expressed genes, synteny between human NPH3 and murine pcy was established, thus generating the hypothesis that both diseases are caused by recessive mutations of homologous genes [12].
• From these results it seems that D2-pcy mice in the early stages of the cystic disease continue to secrete excess protons through the CA-mediated reaction that is stimulated for regulation of acid-base balance in the distal portion of the nephron and the collecting duct in kidney [13].
• Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality [10].

Anatomical context of Nphp3

• FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice [14].
• In the current study, we determined the amount of this nucleotide in intact kidneys, cyst fluid, plasma, and urine in nonazotemic mice (DBA/2FG-pcy/pcy) with a slowly progressive form of inherited polycystic kidney disease (PKD) [4].

Associations of Nphp3 with chemical compounds

• The administration of paclitaxel (100 to 150 micrograms/wk) from 2 to 10 weeks of age to DBA/2FG-pcy/pcy mice with cystic disease had no effect on the increase in kidney weight or on the level of serum urea nitrogen in comparison to untreated cystic animals [2].
• With respect to fatty acid compositions, there were significantly lower levels of docosahexaenoic acid (DHA, 22:6n-3) and higher levels of adrenic acid (AdA, 22:4n-6) in the phospholipids of pcy mouse kidneys [15].
• Significantly higher CA activity was detected in the cytosolic, but not membrane, fraction of kidney homogenates in 5-week-old D2-pcy mice than in age-matched, control DBA/2 (D2) mice, and a more rapid rate of urine acidification was noted in 11-week-old mice when acetazolamide, an inhibitor of the enzyme, was administered orally [13].
• CONCLUSION: Soyasaponin Bb can impede kidney enlargement and cyst growth in the pcy mouse model of PKD [16].
• The phosphatidylinositol-phosphate (PIP) to phosphatidylinositol (PI) molar ratio was higher (0.034 +/- 0.003 vs. 0.023 +/- 0.001, P < 0.01) and the PI-bisphosphate (PIP2) to PIP molar ratio was lower (0.70 +/- 0.08 vs. 1.19 +/- 0.10, P < 0.05) in kidneys of mice with PKD [DBA/2FG-pcy (pcy)] compared with normal controls (DBA/2J) [17].

Other interactions of Nphp3

• These findings strongly suggest that D9Mit14 and D9Mit148 are located near the pcy gene and are good markers for chromosomal walking to this gene [1].
• In contrast, mRNA levels for epidermal growth factor in kidney of DBA/2FG-pcy mice decreased with age as compared with those of DBA/2 mice [18].
• Sodium pump distribution is not reversed in the DBA/2FG-pcy, polycystic kidney disease model mouse [19].
• Complementation analysis indicates that the jck mutation is not allelic with three other known recessive polycystic kidney mutations (cpk and two as yet unnamed mutations), and linkage studies demonstrate it is unlikely to be allelic with a fourth (pcy) [20].
• In the cells lining cysts and/or dilated tubules, CA II activity was well preserved, although the staining intensity was considerably reduced in fully-flattened, lining cells of cysts, but no difference was found between D2-pcy and D2 mice in any segmental localization of renal CA II activity [13].

Analytical, diagnostic and therapeutic context of Nphp3

• Proton magnetic resonance imaging (MRI) and localized spectroscopy techniques were used to study polycystic kidney disease (PKD) in DBA/2FG-pcy (pcy) mice, which are an animal model for the adult form of human PKD [21].
• Using thin-layer and gas-liquid chromatography, we analyzed the lipid components of the kidneys from 120-day-old DBA/2FG-pcy (pcy) having PKD as compared to normal DBA/2J (DBA) mice [15].
• In this study, the activity of carbonic anhydrase (CA) and it histological distribution in the kidney of D2-pcy mice were investigated by immunohistochemistry [13].
• These results show that both dietary protein source and level significantly affect polycystic kidney disease in pcy animals, with the effects of dietary soy protein being most pronounced in female animals fed the low protein diets and the effects of protein reduction being most pronounced in animals fed soy protein-based diets [22].
• A low-fat diet slows progression of renal injury in male and female pcy mice, consistent with findings in the male Han:SPRD-cy rat [5].

References