Glomerular and tubular epithelial defects in kd/kd mice lead to progressive renal failure

Michael P. Madaio, Rexford S. Ahima, Ray Meade, Daniel J. Rader, Alberto Mendoza, Min Peng, John E. Tomaszewski, Wayne W. Hancock, David L. Gasser

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background/Aim: 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 glomerularvisceral 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.

Original languageEnglish (US)
Pages (from-to)604-610
Number of pages7
JournalAmerican Journal of Nephrology
Volume25
Issue number6
DOIs
StatePublished - Nov 2005

Keywords

  • Albuminuria
  • Gene
  • Glomerulus
  • Nephritis
  • Podocyte

ASJC Scopus subject areas

  • Nephrology

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    Madaio, M. P., Ahima, R. S., Meade, R., Rader, D. J., Mendoza, A., Peng, M., Tomaszewski, J. E., Hancock, W. W., & Gasser, D. L. (2005). Glomerular and tubular epithelial defects in kd/kd mice lead to progressive renal failure. American Journal of Nephrology, 25(6), 604-610. https://doi.org/10.1159/000089709