The glomerular visceral epithelial cell (podocyte) is characterized as a specialized structure of the interdigitating foot processes, covering the outer side of the glomerular basement membrane (GBM). The neighboring foot processes are connected by a slit diaphragm, which is a key structure regulating the barrier function of the glomerular capillary wall to prevent proteinuria. We have previously reported that synaptic vesicle protein 2 B (SV2B) is expressed in the podocyte and that the expression is clearly decreased in nephrotic models. However, the precise function of SV2B in the podocyte is unclear. To investigate the role of SV2B in maintaining the podocyte function and to better understand the function of the neuron-like vesicle expressing SV2B in the podocyte, we analyzed them with SV2B knockout (KO) mice. An increase in the amount of proteinuria, effacement of the foot process of the podocyte, and alterations of the GBM were detected in SV2B KO mice. It was also found that the expression of CD2AP, nephrin, and NEPH1, the functional molecules of the slit diaphragm, and laminin, a critical component of the GBM, is clearly altered in SV2B KO mice. Synaptotagmin and neurexin, which have a role in the synaptic vesicle docking in neurons, are downregulated in the kidney cortex of SV2B KO mice. We have previously reported that neurexin interacts with CD2AP, and the present study shows that SV2B interacts with CD2AP. These findings suggest that the SV2B-neurexin complex is involved in the formation and maintenance of the slit diaphragm. In addition, SV2B is densely expressed close to the cell surface in the presumptive podocyte in the early stage of glomerulogenesis. These results suggest that SV2B has an essential role in the formation and maintenance of the glomerular capillary wall. Proteinuria is not only an important symptom of kidney diseases but also an accelerating factor progressing to endstage renal failure. Recent studies showed that proteinuria is also a risk factor for cardiac and cranial vascular events. The glomerulus, a tiny, ball-shaped structure composed of capillaries, is a filtration unit of the kidney, and the glomerular capillary wall functions as a barrier, preventing the leakage of plasma protein into urine. The glomerular capillary wall consists of three layers: an endothelial cell, a glomerular basement membrane (GBM), and a glomerular visceral epithelial cell (podocyte). The main body of the GBM is a meshwork of type IV collagen, and several molecules such as laminin are reported to be critical molecules in the GBM. 1 A podocyte is characterized as a specialized structure of the interdigitating foot processes, covering the outer side of the GBM. The neighboring foot processes are derived from different cell bodies and are connected by a continuous membrane-like structure called a slit diaphragm. [2][3][4] It is now widely accepted that the slit diaphragm is a key structure regulating the barrier function of the glomerular capillary wall and that the dysfunction of the slit diaphragm is...

The effects of traditional Chinese medicine (Sairei‐to) on monoclonal antibody (mAb) inducing proteinuria were examined. Four hundred, 200 and 100mglkg body weight (BW) of Sairei‐to and phosphate‐buffered saline (PBS) as a control were injected intraperitoneally into four groups of female Wistar rats every day from 5 days before intravenous injection of mAb to the end of the experimental period. The amount of urinary protein excretion was significantly suppressed in roughly a dose‐dependent manner. For example, 116.6 ± 89.7mg/day of proteinuria was observed in control groups compared to 4.2 ± 15.2 mglday in the 400 mglkg BW of Sairei‐to treated group 2 days after mAb injection (P < 0.01). Statistically significant (P <0.01) differences were again observed in a repeat experiment (122.1 ± 53.7 vs 10.2 ± 10.1 mglday on the 2nd day) without affecting the glomerular filtration rate. No significant difference was recognized between the total amount of mAb bound to glomeruli 1 h after mAb injection in Sairei‐to‐treated and non‐treated rats, indicating that Sairei‐to pretreatment has no effects on the number or quality of antigenic molecules. The effect of Sairei‐to on a non‐immunological model of proteinuria was also examined. No significant reduction of proteinuria by similar Sairei‐to treatment was observed in aminonucleoside of puromycin nephropathy. The authors conclude that mAb‐induced proteinuria in rats is significantly suppressed by the traditional Chinese medicine, Sairei‐to.

SUMMARYThe effect of chlorpromazine. one of several calmodulin antagonists that inhibit cyloskelelal movement, on the local kinetics oTinjected proteinuria-inducing MoAb 5-1-6 was examined to test the hypothesis that proteinuria is inhibited if the antigen recognized by MoAb 5-1-6 or injected MoAb remains on the surface of epithelial foot processes. MoAb 5-1-6 was injected into both chlorpromazine-treated (5 mg/100 g body weight) and untreated rats. As a positive control for the chlorproma/ine treatment, anti-FxlA serum was also injected into other ehlorpromazine-treated and untreated rats. Chlorpromazine inhibited neither the change in loealization of injected MoAb 5-1-6 nor proteinuria, although it showed an inhibitory effect on redistribution of immune complex and the fixation of complement in passive Heymann glomerulonephritis induced by injection of anti-FxIA serum. We conclude that the kinelics of bound MoAb 5-1-6 arc regulated by a system different from that Of>erating in passive Heymann glomerulonephritis.

Apolipoprotein (a) [apo(a)] may interfere with the fïbrinolytic system because of its structural similarity to plasminogen. In the present study, we evaluated the effect of glomerular deposition of apo(a) on coagulation and fibrinolysis in patients with glomerular diseases. Twenty-four patients (13 males and 11 females) with various glomerulopathies were studied. We examined renal biopsy specimens for the presence of apo(a), and investigated the relationship between the glomerular deposition of apo(a) and coagulation and fibrinolysis within the glomeruli. The patients who exhibited the deposition of apo(a) (group A) had a significantly higher incidence of deposition of apo B-100 and low-density lipoprotein (LDL) receptor, and a significantly lower incidence of deposition of plasmin-α₂-plasmin inhibitor complexes (PIC) and tissue-type plasminogen activator than did patients without apo(a) deposition (group B). Patients in group A had a significantly higher level of serum total cholesterol and lipoprotein (a) than did patients in group B. Plasma levels of PIC and D-dimer in group A were significantly lower than those in group B. The plasma level of thrombin-antithrombin III complexes in group A was significantly higher than that in group B. These findings suggest that glomerular apo(a) deposition plays a part in coagulation and fibrinolysis within the glomeruli in patients with glomerular diseases.

SUMMARYBy immunization with rabbit immunoglobulins and the injection of a subnephritogenic dose of rabbit nephrotoxic serum (NTS), accelerated-type nephrotoxic serum nephritis (NTN) was induced in heterozygous (rnu +) rats but not in athymic nude (rnu/rnu) rats. By transferring rat antibody against rabbit immunoglobulins, marked proteinuria was induced also in nude rats (202 0 + 98 4 mg/ day on day 3) as in rnu/+ rats (122 6+ 35 3 mg/day on day 3). No marked differences in histological findings could be found between both groups. The most marked increase in the number of intraglomerular infiltrating cells was observed in heterozygous rats indicating that the presence of thymus-derived cells leads to the accumulation of more cells in glomeruli. We conclude that humoral immunity alone is enough to accelerate the pathogenic mechanism which induces glomerular injury with heavy proteinuria in this model.