Analysis Tools
mortality/aging
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• heterozygous matings yield homozygotes at a reduced Mendelian ratio (17% vs expected 25%)
• however, viability is normal after birth
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renal/urinary system
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• glomerular cysts first develop at 3 months of age; they are distributed throughout the cortex area and are characterized by enlarged Bowman's space lined by flattened PECs and retracted capillary tufts
• % of glomeruli with cystic changes is significantly increased at 6 months and also at 12 months
• however, glomerulotubular junction is preserved in glomeruli with cystic change
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• no significant increase in urine osmolality under water deprivation at 6 months of age, indicating a urinary concentration defect
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• mild but significant increase in urine albumin/creatinine ratio at 6 and 12 months of age
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albuminuria
(
J:240798
)
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• at P0, mean urinary albumin concentration is 942.0 +/- 507.5 mg/l versus 34.6 +/- 7.8 in wild-type controls
• urine albumin excretion is progressively reduced during the first week of age, with recovery of the glomerular and tubular lesions at P7
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• numerous urinary dysmorphic erythrocytes found at P0, suggestive of glomerular origin
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• expansion of the stroma component between ducts at P0
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• flattened epithelium in the collecting ducts at P0
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• widening of the collecting duct lumen in the medulla at P0
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• adult mice show thickening and multilamination of the Bowman's capsule at 6 months of age
• abnormal Bowman's capsule structure is associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells
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• glomerular parietal epithelial cells (PECs) show an activated phenotype (overexpression of claudin-1 and induction of CD44), induction of DDR1 (discoidin domain receptors 1), and activation of integrin-linked kinase (ILK) pathway at 1 month of age, prior to the development of glomerular cysts and periglomerular inflammation
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• at 1 month of age, PECs in a subset (~15%) of glomeruli appear cube-shaped with enlarged nuclei, instead of forming a monolayer of thin epithelial cells with flat nuclei as in normal PECs
• enlarged cuboid PECs with enlarged nuclei are found lining the Bowman's capsule in about one-third of non-cystic glomeruli at 6 and 12 months of age
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• enlarged Bowman's spaces with retracted capillary tufts found in a subset of glomeruli at P0
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• podocyte disorganization in immature glomeruli after the formation of the first capillary loops, with podocytes arranging in multilayers instead of forming a regular layer
• focal persistence of large intercellular junctions between podocytes at P0
• integrin-linked kinase (ILK) expression is strongly enhanced in podocytes at 1 and 6 months of age
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• extensive podocyte foot process effacement in mature glomeruli at P0
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• expression of nephrin is dramatically reduced in glomeruli at P0; although occasionally detected in slit diaphragms, nephrin is abnormally localized in cytoplasmic vacuoles (vesicles) within the podocytes
• in contrast, podocin is normally expressed in the basal region of the podocytes along the GBM
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• segmental duplication of the glomerulus basement membrane (GBM) at P0
• however, GBM and the tubular BM appear normal at 6 months of age
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• glomerulogenesis is delayed after the formation of the first capillary loops, with defective GBM and podocyte maturation resulting in neonatal glomerular hyperpermeability
• neonate glomerular defects are resolved within the first month of life, but glomerular cysts develop at 3 months of age
• adult mice develop glomerulocystic kidney disease; however, no glomerular crescent or sclerotic segment of the glomerular tuft is observed
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• dilated glomerular capillaries found in mature glomeruli in the deep cortex at P0
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• integrin-linked kinase (ILK) expression is strongly enhanced in the mesangium at 1 and 6 months of age
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• newborns display delayed glomerulogenesis and podocyte differentiation without reduction of nephron number
• however, neonate kidney defects do not result in a decreased glomerular density in adult mice
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• dysmorphic kidney papilla at 6 months of age
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• dilated proximal tubular sections with flattened epithelial cells at P0
• intracytoplasmic eosinophilic vacuoles in proximal tubular cells
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• focal dilation with flattened proximal tubule cells at P0
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renal cast
(
J:240798
)
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• erythrocyte casts found in tubular sections at P0 and persisting at P7
• however, no casts are observed at 1 month of age
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• in situ gelatin zymography revealed enhanced matrix metalloproteinase (MMP) enzymatic activity in the periglomerular region and around the renal tubules at 6 months of age
• pretreatment of renal tissue with EDTA, a specific inhibitor of MMP2 and MMP9, blocked gelanolytic activity
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• inflammatory infiltrates are first detected in the kidney at 3 months of age
• at 12 months of age, periglomerular and perivascular inflammatory infiltrates are mostly composed by T-lymphocytes surrounded by macrophages
• however, no significant fibrosis is noted, except in inflammatory areas, and tubules remain normal at 12 months
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• polyuria both under basal and water deprivation conditions at 6 months of age
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homeostasis/metabolism
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• significant increase of serum urea at 6 months but not at 12 months of age
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• expression of the mutant alpha1alpha1alpha2(IV) trimer is reduced in newborn kidneys at P0, but remains detectable in the mesangium, Bowmans capsule, tubular BM, and GBM, indicating partially altered alpha1alpha1alpha2(IV) secretion
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• no significant increase in urine osmolality under water deprivation at 6 months of age, indicating a urinary concentration defect
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• mild but significant increase in urine albumin/creatinine ratio at 6 and 12 months of age
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albuminuria
(
J:240798
)
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• at P0, mean urinary albumin concentration is 942.0 +/- 507.5 mg/l versus 34.6 +/- 7.8 in wild-type controls
• urine albumin excretion is progressively reduced during the first week of age, with recovery of the glomerular and tubular lesions at P7
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• numerous urinary dysmorphic erythrocytes found at P0, suggestive of glomerular origin
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immune system
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• inflammatory infiltrates are first detected in the kidney at 3 months of age
• at 12 months of age, periglomerular and perivascular inflammatory infiltrates are mostly composed by T-lymphocytes surrounded by macrophages
• however, no significant fibrosis is noted, except in inflammatory areas, and tubules remain normal at 12 months
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growth/size/body
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• significantly reduced mean body weight in both sexes at 6 and 12 months of age
• however, mean kidney weight is normal at both ages
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• glomerular cysts first develop at 3 months of age; they are distributed throughout the cortex area and are characterized by enlarged Bowman's space lined by flattened PECs and retracted capillary tufts
• % of glomeruli with cystic changes is significantly increased at 6 months and also at 12 months
• however, glomerulotubular junction is preserved in glomeruli with cystic change
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cardiovascular system
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• dilated glomerular capillaries found in mature glomeruli in the deep cortex at P0
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• adults exhibit retinal tortuosity
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• newborns exhibit brain hemorrhages
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muscle
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• adults exhibit muscular dystrophy
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nervous system
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• newborns exhibit brain hemorrhages
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vision/eye
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• adults exhibit retinal tortuosity
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| kidney disease | DOID:557 | J:240798 | ||
