Phenotypes Associated with This Genotype

Genotype
MGI:5432357

• Allelic Composition: Ilk^tm1Star/Ilk^tm1Star; Tg(NPHS2-cre)295Lbh/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

decreased survivor rate ( J:129286 )

• only a few mice survive beyond 6 months of age

premature death ( J:129244 , J:129286 )

• mice exhibit a reduced life span with a median age of death at 19 weeks, and 100% mortality by 32 weeks of age (J:129244)

• mice begin to die at 10 weeks of age; most die of renal failure at ~3-4 months of age (J:129286)

growth/size/body

decreased body weight ( J:129286 )

• significantly decreased body weight first noted at 10 weeks of age

renal/urinary system

detached podocyte ( J:129244 , J:129286 )

• focal detachment from the basement membrane at 8-12 weeks of age (J:129244)

• by 10 weeks of age, podocytes are sometimes detached from the GBM and found in the lumens of dilated tubules (J:129286)

• however, no podocyte detachment is observed at 4 weeks of age (J:129286)

increased kidney apoptosis ( J:129286 )

• marked apoptosis in the tubulointerstitial area of the kidney at 10 weeks of age, unlike in control mice

increased podocyte apoptosis ( J:129286 )

• a significant number of TUNEL+ podocytes is noted in the lumens of tubules at 10 weeks of age, suggesting that detached podocytes undergo apoptotic death

• however, no podocyte detachment or apoptosis is observed at 4 weeks of age, when albuminuria is pronounced

increased urine protein level ( J:129244 , J:129286 )

• selective albuminuria first detected at 2 weeks that progresses rapidly to unselective proteinuria by 4-12 weeks of age (J:129244)

• massive proteinuria at 12 weeks of age (J:129244)

• significantly increased urine total protein at 4 and 10 weeks of age (J:129286)

albuminuria ( J:129244 , J:129286 )

• selective albuminuria first seen at 2 weeks of age (J:129244)

• albuminuria precedes the development of focal segmental glomerulosclerosis lesions (J:129244)

• dramatically increased urine albumin levels are first noted at 4 weeks of age, progressing to severe albuminuria at 10 weeks of age (J:129286)

tubulointerstitial nephritis ( J:129244 , J:129286 )

• tubulointerstitial changes with mononuclear infiltration at 12 weeks of age (J:129244)

• advanced tubulointerstitial inflammation in end-stage kidneys (J:129244)

• mild, patchy mononuclear inflammatory infiltrate in the interstitium at 10 weeks of age (J:129286)

abnormal kidney morphology ( J:129244 )

• at 16 weeks of age, nephrotic end-stage kidneys appear yellow and display a rough surface

abnormal podocyte morphology ( J:129244 , J:129286 )

• occasional prominent single podocytes, predominantly in juxtamedullary glomeruli at 2-3 weeks of age (J:129244)

• prominent podocytes in juxtamedullary glomeruli with pseudocysts and vacuolization, focal microvillous transformation, and multifocal foot process effacement at 4 weeks of age (J:129244)

• advanced vacuolization, microvillous transformation, widespread foot process effacement, and focal detachment from the basement membrane at 8-12 weeks of age (J:129244)

• at 4 weeks of age, an aberrant distribution of nephrin and alpha-actinin-4 is observed, unlike in control podocytes; however, the localization of podocin and synaptopodin remains intact (J:129286)

fused podocyte foot processes ( J:129286 )

• fused foot processes are noted at 10 weeks of age

podocyte foot process effacement ( J:129244 , J:129286 )

• multifocal foot process effacement at 4 weeks of age (J:129244)

• widespread foot process effacement at 8-12 weeks of age (J:129244)

• slight podocyte foot process effacement with a narrower slit diaphragm is occasionally seen at 2 weeks of age, prior to the onset of albuminuria (J:129286)

• marked foot process effacement is noted at 4 weeks of age, and becomes severe by 10 weeks of age (J:129286)

abnormal podocyte slit diaphragm morphology ( J:129244 , J:129286 )

• loss of slit diaphragm noted with progression to unselective proteinuria (J:129244)

• at 4 weeks of age, foot processes are adhered to GBM as continuous cytoplasmic processes, leading to the disappearance of the slit diaphragm (J:129286)

• a narrower slit diaphragm is occasionally found in some podocyte areas at 2 weeks of age (J:129286)

decreased podocyte number ( J:129286 )

• a ~70% reduction in the number of podocytes per glomerulus is first seen at 10 weeks of age

podocyte microvillus transformation ( J:129244 , J:129286 )

• focal microvillous transformation at 4 weeks of age (J:129244)

• at 4 weeks of age, massive microvilli are formed on the surface of podocytes, unlike in control podocytes (J:129286)

abnormal renal glomerulus basement membrane morphology ( J:129244 , J:129286 )

• no alterations in key GBM components (fibronectin, laminins, and collagen IV isoforms) are observed; however, alpha3-integrins are relocalized into a granular pattern along the GBM, consistent with altered integrin-mediated matrix assembly, at 3 weeks of age (J:129244)

• at 10 weeks of age, podocyte foot processes are sometimes detached from the GBM, leading to a naked GBM on the side of the Bowman space (J:129286)

• an irregular GBM shape is also observed in some areas of the glomeruli at 4 weeks of age (J:129286)

increased renal glomerulus basement membrane thickness ( J:129244 , J:129286 )

• homogeneous thickening of the GBM at 3 weeks of age (J:129244)

• true harmonic mean GBM thickness is increased by 22.6% at 3 weeks of age (J:129244)

• diffuse and irregular thickening of the GBM with electron-lucent areas at 8-12 weeks of age (J:129244)

• increased GBM thickness is observed in some areas of the glomeruli at 4 weeks of age (J:129286)

abnormal renal glomerulus morphology ( J:129286 )

• primary glomerular lesions first seen at 10 weeks of age

abnormal glomerular capillary morphology ( J:129244 )

• distorted capillaries at 4 and 12 weeks of age

expanded mesangial matrix ( J:129244 , J:129286 )

• occasional segmental mesangial expansion with increased matrix deposition at 4 weeks of age (J:129244)

• advanced mesangial expansion with increased matrix deposition at 12 weeks of age (J:129244)

• moderate to marked mesangial expansion at 10 weeks of age (J:129286)

glomerulosclerosis ( J:129244 , J:129286 )

• mice develop progressive focal segmental glomerulosclerosis (J:129244)

• advanced focal and segmental sclerotic lesions associated with tubulointerstitial changes at 8-16 weeks of age (J:129244)

• diffuse glomerulosclerosis in end-stage kidneys (J:129244)

• segmental glomerulosclerosis to global sclerosis at 10 weeks of age (J:129286)

glomerular crescent ( J:129244 )

• crescent formation at 12 weeks of age

renal glomerular synechia ( J:129244 )

• tuft adhesions to Bowman's capsule at 12 weeks of age

renal glomerulus hypertrophy ( J:129286 )

• enlarged glomerular size at 10 weeks of age

renal interstitial fibrosis ( J:129244 , J:129286 )

• at 12 and 16 weeks of age (J:129244)

• mild interstitial fibrosis at 10 weeks of age (J:129286)

renal tubule atrophy ( J:129244 )

• at 12 weeks of age

dilated renal tubule ( J:129286 )

• extensive tubular dilation distended by proteinaceous fluid and cellular debris at 10 weeks of age

abnormal glomerular filtration barrier function ( J:129244 )

• progressive filtration barrier failure

kidney failure ( J:129244 , J:129286 )

• mice die of kidney failure (J:129244)

• age-dependent deterioration of kidney function (J:129286)

homeostasis/metabolism

increased circulating creatinine level ( J:129286 )

• significantly increased serum creatinine levels at 10 but not at 4 weeks of age

increased blood urea nitrogen level ( J:129244 )

• at 12 weeks of age

increased circulating cholesterol level ( J:129244 )

• at 12 weeks of age

increased urine protein level ( J:129244 , J:129286 )

• selective albuminuria first detected at 2 weeks that progresses rapidly to unselective proteinuria by 4-12 weeks of age (J:129244)

• massive proteinuria at 12 weeks of age (J:129244)

• significantly increased urine total protein at 4 and 10 weeks of age (J:129286)

albuminuria ( J:129244 , J:129286 )

• selective albuminuria first seen at 2 weeks of age (J:129244)

• albuminuria precedes the development of focal segmental glomerulosclerosis lesions (J:129244)

• dramatically increased urine albumin levels are first noted at 4 weeks of age, progressing to severe albuminuria at 10 weeks of age (J:129286)

immune system

tubulointerstitial nephritis ( J:129244 , J:129286 )

• tubulointerstitial changes with mononuclear infiltration at 12 weeks of age (J:129244)

• advanced tubulointerstitial inflammation in end-stage kidneys (J:129244)

• mild, patchy mononuclear inflammatory infiltrate in the interstitium at 10 weeks of age (J:129286)

cardiovascular system

abnormal glomerular capillary morphology ( J:129244 )

• distorted capillaries at 4 and 12 weeks of age

cellular

detached podocyte ( J:129244 , J:129286 )

• focal detachment from the basement membrane at 8-12 weeks of age (J:129244)

• by 10 weeks of age, podocytes are sometimes detached from the GBM and found in the lumens of dilated tubules (J:129286)

• however, no podocyte detachment is observed at 4 weeks of age (J:129286)

increased kidney apoptosis ( J:129286 )

• marked apoptosis in the tubulointerstitial area of the kidney at 10 weeks of age, unlike in control mice

increased podocyte apoptosis ( J:129286 )

• a significant number of TUNEL+ podocytes is noted in the lumens of tubules at 10 weeks of age, suggesting that detached podocytes undergo apoptotic death

• however, no podocyte detachment or apoptosis is observed at 4 weeks of age, when albuminuria is pronounced