title: Glomerular and tubular epithelial defects in kd/kd mice lead to progressive renal failure.
abstract: OBJECTIVE
  The kd/kd mouse spontaneously develops severe and progressive nephritis leading to renal failure, characterized by cellular infiltration, tubular destruction and glomerular sclerosis. Recent identification of the mutant gene and the observation that podocytes are affected, led to the hypothesis that there are primary renal epithelial cell defects in this strain.
  
  
  METHODS
  Clinical and pathological signs of disease in a large cohort of kd/kd mice were studied by light microscopy, electron microscopy, and biochemical analyses of serum and urine at early stages of disease. Special attention was paid to mice under 140 days of age that had normal blood urea nitrogen (BUN) levels, but had developed albuminuria.
  
  
  RESULTS
  Although overt glomerular abnormalities are commonly observed either coincident with or after tubulointerstitial nephritis, we now report that albuminuria and visceral epithelial abnormalities, including hyperplasia and podocyte effacement may occur before the onset of either elevated BUN levels or severe interstitial nephritis, and this is accompanied by biochemical perturbations in serum typical of the nephrotic syndrome.
  
  
  CONCLUSIONS
  The results suggest that the defect in kd/kd mice primarily affects both the tubular and glomerular visceral epithelium. The tubular epithelial defect triggers autoimmune interstitial nephritis, whereas a defect in podocytes leads to proteinuria and glomerulosclerosis. Thus, a single mitochondrial abnormality may result in differences in disease expression that vary with the type of epithelial cells. It is likely that the mitochrondrial perturbations in glomerular and tubular epithelia act in concert, through activation of different pathologic pathways, to accelerate disease progression leading to renal failure.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: Ray
authors.initials: R
authors.lastname: Meade
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Alberto
authors.initials: A
authors.lastname: Mendoza
authors.forename: Min
authors.initials: M
authors.lastname: Peng
authors.forename: John E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: David L
authors.initials: DL
authors.lastname: Gasser
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D004847:Epithelial Cells / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000473:pathology* / Q000652:urine; D007678:Kidney Glomerulus / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D009395:Nephritis, Interstitial / Q000097:blood / Q000473:pathology* / Q000652:urine; D009404:Nephrotic Syndrome / Q000097:blood / Q000473:pathology / Q000652:urine; D050199:Podocytes / Q000473:pathology; D011507:Proteinuria / Q000097:blood