Molecular Characterization of Fibrotic Scarring in Kidneys with Congenital Nephrotic Syndrome of the Finnish type

Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal recessive disease, enriched in the Finnish population. NPHS1 is caused by a mutation in the NPHS1 gene. This gene encodes for nephrin, which is a major structural component of the slit diaphragm connecting podocyte foot processes in the glomerular capillary wall. In NPHS1, the genetic defect in nephrin leads to heavy proteinuria already in the newborn period. Finnish NPHS1 patients are nephrectomized at infancy, and after a short period of dialysis the patients receive a kidney transplant, which is the only curative therapy for the disease. In this thesis, we examined the cellular and molecular mechanisms leading to the progression of glomerulosclerosis and tubulointerstitial fibrosis in NPHS1 kidneys. Progressive mesangial expansion in NPHS1 kidneys is caused by mesangial cell hyperplasia and the accumulation of extracellular matrix proteins. Expansion of the extracellular matrix was caused by the normal mesangial cell component, collagen IV. However, no significant changes in mesangial cell phenotype or extracellular matrix component composition were observed. Endotheliosis was the main ultrastructural lesion observed in the endothelium of NPHS1 glomeruli. The abundant expression of vascular endothelial growth factor and its transcription factor hypoxia inducible factor-1 alpha were in accordance with the preserved structure of the endothelium in NPHS1 kidneys. Hypoperfusion of peritubular capillaries and tubulointerstitial hypoxia were evident in NPHS1 kidneys, indicating that these may play an important role in the rapid progression of fibrosis in the kidneys of NPHS1 patients. Upregulation of Angiotensin II was obvious, emphasizing its role in the pathophysiology of NPHS1. Excessive oxidative stress was evident in NPHS1 kidneys, manifested as an increase expression of p22phox, superoxide production, lipid oxide peroxidation and reduced antioxidant activity. In conclusion, our data indicate that mesangial cell proliferation and the accumulation of extracellular matrix accumulation are associated with the obliteration of glomerular capillaries, causing the reduction of circulation in peritubular capillaries. The injury and rarefaction of peritubular capillaries result in impairment of oxygen and nutrient delivery to the tubuli and interstitial cells, which correlates with the fibrosis, tubular atrophy and oxidative stress observed in NPHS1 kidneys.