Abstract. Excessive proteinuria due to loss of glomerular permselectivity in nephrotic syndrome can cause disturbances in renal salt and water handling with edema formation. Apart from oncotic and hydrostatic mechanisms associated with hypoalbuminemia, primary derangements in renal tubular sodium transport may contribute to the pathogenesis of nephrotic edema. Whereas there is evidence for an increase of cortical collecting duct sodium reabsorption in nephrotic rats, it remains controversial whether proximal tubule sodium transport may also be activated in this condition. The regulation of the cortical Na/H exchanger NHE3, the main pathway for Na reabsorption in the proximal tubule (PT), was investigated in rats with puromycin aminonucleoside (PAN)-induced nephrotic syndrome. PAN rats developed reduced GFR, severe proteinuria, and sodium retention within 3 d. After 10 d, immunoblots of brush border vesicles revealed a decreased abundance of NHE3 in nephrotic animals. However, the Na/H antiporter activity in the same vesicle preparations was not significantly altered. Antiporter activity normalized for NHE3 protein was increased by 88% in nephrotic animals (P ϭ 0.025). Immunohistochemistry with the same polyclonal antibody as for immunoblots revealed a decrease of NHE3 abundance in PT. In contrast, immunoreactivity for the monoclonal antibody 2B9, which specifically recognizes the non-megalin-associated, transport-competent pool of NHE3, was higher in PANtreated rats than in controls. In conclusion, increased sodium reabsorption might be associated with a shift of NHE3 from an inactive pool to an active pool, thus contributing to sodium retention in a state of proteinuria.

Recent observations suggest a central role of podocytes in crescent formation. In experimental glomerulonephritis podocytes disrupt the parietal epithelial layer and attach on its basement membrane, thus forming bridges between the tuft and Bowman's capsule, and they are a major constituent of crescents. In order to explain these findings we hypothesize that inflammation triggers motility in podocytes. In the present study we asked whether podocytes display alterations which suggest a migratory behavior in glomerulonephritis. Glomerulonephritis was induced in mice by injection of a rabbit serum against the glomerular basement membrane. The kidneys were perfusion-fixed 6 days later and examined by light and electron microscopy as well as by immunohistochemistry. In glomerulonephritis the apical cytoplasm of podocytes displayed numerous actin-containing microprotrusions. Cortactin, a protein involved in the regulation of actin polymerization, was predominantly expressed in foot processes of podocytes in control mice. It was redistributed to the cell body in glomerulonephritis. In untreated mice betal-integrin was restricted to the foot processes. In glomerulonephritis it was additionally found in the cytoplasm and in the apical cell membrane. Recycling of integrins is a crucial event in initiation of cell migration. ICAM-1 and CD44, the ligation of which induces migratory behaviors, were absent from healthy podocytes but expressed by some podocytes in glomerulonephritis. Thus, in glomerulonephritis podocytes display some characteristic features of migrating cells. This might explain their ability to break through the parietal epithelium and to become a constituent of early crescents.

In a similar manner as described earlier for focal segmental glomerulosclerosis, in crescentic glomerulonephritis nephron loss can be initiated by the progression of a glomerular lesion into the proximal tubule. Interstitial inflammation might be rather a consequence than the cause of tubular degeneration.