Altered gene expression and functions of mitochondria in human nephrotic syndrome

The molecular basis of glomerular permselectivity remains largely unknown. The congenital nephrotic syndrome of the Finnish type (CNF) characterized b y massive proteinuria already present but without extrarenal symptoms is a unique human disease model of pure proteinuria, In search of genes and path ophysiologic mechanisms associated with proteinuria, we used differential d isplay-PCR to identify differences in gene expression between glomeruli fro m CNF and control kidneys, A distinctly underexpressed PCR product of the C NF kidneys showed over 98% identity with a mitochondrially encoded cytochro me c oxidase (COX I), Using a full-length COX I cDNA probe, we verified dow n-regulation of COX I mRNA to 1/4 of normal kidney values on Northern blots , In addition, transcripts of other mitochondrially encoded respiratory cha in complexes showed a similar down-regulation whereas the respective nuclea rly encoded complexes were expressed at comparable levels, Additional studi es using histochemical, immunohistochemical, in situ hybridization, RT-PCR, and biochemical and electron microscopic methods all showed a mitochondria l involvement in the diseased kidneys but not in extrarenal blood vessels, As a secondary sign of mitochondrial dysfunction, excess lipid peroxidation products were found in glomerular structures in CNF samples, Our data sugg est that mitochondrial dysfunction occurs in the kidneys of patients with C NF, with subsequent lipid peroxidation at the glomerular basement membrane, Our additional studies have revealed similar down-regulation of mitochondr ial functions in experimental models of proteinuria, Thus, mitochondrial dy sfunction may be a crucial pathophysiologic factor in this symptom.