Focal adhesion kinase (p125^FAK) is a novel non-receptor cytosolic tyrosine kinase which is activated through the phosphorylation of its tyrosine residue by ligands that bind to integrins and ligands that activate protein kinase C (PKC). In diabetic glomeruli, extracellular matrix proteins such as fibronectin, laminin and type IV collagen, which bind to integrins, were found to be increased in the mesangial area. Furthermore, PKC was shown to be activated in diabetic glomeruli. These changes might be able to cause the activation of p125^FAK in diabetic glomeruli. To test this hypothesis, we examined tyrosine phosphorylation of p125^FAK and paxillin, a proposed substrate of p125^FAK, in glomeruli isolated from streptozotocin (STZ)-induced diabetic rats. Tyrosine phosphorylation of p125^FAK or paxillin was evaluated by immunoblot analysis using anti-phosphotyrosine antibody after immunoprecipitation with anti-p12^FAK or anti-paxillin antibody. Three and seven weeks after STZ injection, tyrosine phosphorylation of both p125^FAK and paxillin was increased in diabetic glomeruli. The increase in tyrosine phosphorylation of p125^FAK and paxillin was not observed in glomeruli from diabetic rats treated with insulin. To investigate the mechanism of increase in tyrosine phospho rylation of p125^FAK, we examined tyrosine phosphorylation of p125^FAK in mesangial cells plated on a fibronectin-coated dish or cultured under conditions of high glucose concentration (conditions under which PKC can be activated). Attachment of the cells to fibronectin induced tyrosine phosphorylation of p125^FAK, whiLe a high gLucose concentration did not modulate tyrosine phosphoryLation of p125^FAK. In conclusion, tyrosine phosphorylation of p125^FAK and paxillin was increased in diabetic glomeruli and these alternations may have been caused by changes in extracellular matrix proteins in diabetes.

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It is an established fact that animals recovering from prior acute renal failure (ARF) are resistant to subsequent renal failure challenge with the same toxic agents, although the detailed mechanisms responsible for this phenomenon remain unclear. In this study, the mechanism underlying acquired resistance to gentanmicin (GM) was investigated from the viewpoint of kidney tissue enzymology. Sprague-Dawley rats (N=40) were administered GM subcutaneously at the dose of 80mg /day consecutively for 40 days. Blood urea nitrogen (BUN) reached the maximum mean concentration of 36 mg/dl on day 14. Thereafter, it decreased to a level within the normal range on day 21. The change in fractional excretion of sodium (FENa) showed a curve virtually identical to the change in BUN. In renal tissue, the elevation of malondialdehyde (MDA) levels was transient during continued administration of GM. The shingomyelin (SPH)/phosphatidylcholine (PC) ratio significantly decreased on day 4, but there was no marked change thereafter. The levels of total phospholipids (PLs), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) increased, whereas SPH decreased mostly on day 4. The levels of phosphatidylinositol (PI) showed a continued fall during the 40 days of the experiment. On day 40, these changes in composition recovered. Phospholipase A2 (PLA2) activities decreased gradually, whereas a distinct increase in phospholipase c (PLC) activity was maintained after day 21. Furthermore, glutathione (GSH) levels also showed two distinct cycles of decrease and increase. PLs levels correlated well with PLC activities. It was concluded that accelerated lipid peroxidation occurs early in the course of GM administration and enhances changes in the phospholipid composition, which has an influence on membrane fluidity. Thus, acquired resistance to ARF induced by GM may be due to the supply of GSH and the maintenance of alteration in phospholipid composition, which are induced by PLC activities.

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In order to obtain a useful index that can predict the effectiveness of steroid therapy in IgA nephropathy, we investigated the relationship between steroid therapy and extracapillary change. We analysed 51 cases consisting of a group of 24 cases in which steroid was administered (initial dose: prednisolone 20-60mg/day orally, or pulse therapy), and a group of 27 cases in which steroid was not administered. First of all, we compared these two groups in terms of a clinical improvement rate over 3, 12 and 60-month-periods after the therapy, respectively. It was found that steroid therapy led to a higher improvement rate (p<0.01-0.05), indicating that steroid is effective for IgA nephropathy-Among the group undergoing steroid therapy, the frequency of cellular crescents (C) was signifi cantly higher (p<0.05-0.01) in the cases in whom steroid was effective and that of fibrous crescents or adhesion (F) was significantly lower (p<0.05-01). We then assessed C/F in each case of the steroid-administered group, and studied its relationship with the improvement rate. As a result, the improvement rate was below 50% in the group of C/F<0.25, over 50% of the group of 0.25≤C/ F<0.75, and 100% of the group of 0.75≤C/F. Accordingly, we concluded that C/F could be used a parameter for predicting the effectiveness of steroid therapy in IgA nephropathy and for determining indications for steroid therapy.

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We conducted an immunohistological investigation on the pathogenesis of interstitial foam cell formation in patients with idiopathic membranous nephropathy (MN). The patients were divided into two groups: Group I consisted of 23 MN patients with interstitial foam cells; Group II consisted of the other 159 patients without foam cells. Age at renal biopsy, duration of proteinuria, blood pressure and other clinical parameters were not significantly different between the two groups. The proportion of nephrotic patients in Group I was 52.2% (12/23), and was not significantly different from that in Group II (48.4%, 77/159). Renal biopsy specimens were examined by immunoperoxidase studies using monoclonal antibodies. The interstitial foam cells were positive for EBM11 (CD68) and 25F9, which are markers of macrophage (Mφ) and mature Mφ, respectively, but did not express markers of T cells. In interstitial infiltrating cells, both Mφ and T cells were observed, but mature Mφ were seldom seen. Furthermore, LFA-1 and ICAM-1, but not ICAM-3 (the third ligand for LFA-1) were observed in the interstitial foam cells. LFA-1 and ICAM-3 were observed mainly in interstitial infiltrating cells, but ICAM-1 was observed to a much lesser extent in these cells. These results suggest that interstitial foam cells in MN may be independent of severe hyperlipidemia and proteinuria, and that there may be different mechanisms underlying the accumulation of interstitial foam cells and infiltrating mφs. Further investigations are required to clarify the pathogenesis of interstitia1 foam ce11s in renal tissue.

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We report here a 19-year-old man with intractable nephrotic syndrome due to focal glomerulosclerosis (FGS) treated by low-density lipoprotein apheresis (LDL-A). The patient had been receiving several drugs, including steroids, cyclophosphamide, mizoribine and deoxysparguarine, for the past ten years, but the nephrotic syndrome was resistant to these drugs. Although the initial renal biopsy specimen showed minimal change-type lesions, the second biopsy specimen obtained 6 years later revealed typical FGS findings accompanied by lipid deposition (apoB) and macrophage infiltration (CD68) in the involved area. LDL-apheresis was performed ten times per course using a dextran sulfate cellulose column (Liposorba LA-15) as the LDL absorber and polysulfone hollow-fibers (Sulflux) as the plasma separator, processing a total of 3, 000 ml of plasma during each apheresis. After treatment the serum levels of LDL and total cholesterol decreased to 50% and 58% of their initial levels, respectively. Immediately after the first course of treatment, the renal dysfunction did not improve, but a decrease in urinary protein was observed (from 43.7 g/day to 8 g/day). Two months later, because urinary protein increased and renal function decreased (Ccr7ml/min), a second course of treatment was started. However, his renal dysfunction did not improve and urinary protein did not decrease. In conclusion, in FGS with-progressive renal failure, renal histological findings of positive APO-B, CD68 (macrophage) in sclerotic lesion may be indications of effective LDL-apheresis.

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A 50-year-old male was admitted to our hospital because of proteinuria, thrombocytopenia and moderate renal dysfunction. On admission, he had massive ascites, which was transudatory. During his clinical course, renal function deteriorated and the urine volume was decreased. Hemolytic uremic syndrome with massive ascites was diagnosed based on the finding of thrombocytopenia, acute renal failure and hemolytic anemia. Methylpredonisolone pulse therapy was not effective, but plasma exchange given 22 times in total combined with vincristine sulfate, PGI₂ analogue and vitamin E administration was very effective for thrombocytopenia, renal dysfunction and hemolytic anemia. Massive ascites disappeared at the same time. After complete recovery of renal function, renal biopsy was performed, revealing the reticulation of mesangial matrix and mesangiolysis, which correspond to hemolvtic uremic syndrome.

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Goodpasture's syndrome has been reported as a disease that has a favorable prognosis when the patient receives intensive immunosuppressive drug-therapy from an early stage after onset. The present report describes a 50-year-old woman, who exhibited progressive renal failure accompanied by pulmonary hemorrhage, and an increase in serum level of antiglomerular basement membrane (GBM) antibody. Initial histological examination of a renal specimen indicated a severe fibrocellular crescentic glomerulonephritis with a linear deposition of Ig-G and C₃ along the glomerular capillary wall. The patient was thus diagnosed as having Goodpasture's syndrome. Therapy with pulse treat ment of steroid (corticosteroid hormone), immunosuppressive agents, or plasma-exchange for the removal of anti-GBM antibody was adopted a week after the clinical onset. However, histological amelioration of the glomeruli did not occur with this treatment in the second biopsy, while glomerular damage advanced progressively. In contrast to other patients with Goodpasture's syndrome, our caserevealed an unfavorable outcome regardless of receiving intensive therapy from an early period after onset, which suggests that more intensive therapy of another approach to this patient may have been necessary.

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Mitochondrial encephalomyopathy is a hereditary syndrome showing impairment of muscle and the central nervous system. In this disorder, the following three syndromes have been identified on the basis of characteristic symptoms: Kearns-Sayre syndrome (KSS), mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS), and myotonic epilepsy with ragged-red fibers (MERRF). In this report, we describe a case of mitochondrial encephalomyopathy with renal disease. A 25-year-old man was referred to our hospital in May, 1992 for evaluation of long-standing proteinuria. He had a small stature, exotropia and no pretibial edema. No mental retardation was r observed. Urinary protein excretion was 2.0g/day and urine sugar was negative. Laboratory examina tion revealed a serum urea nitrogen 19 mg/dl, and a creatinine value of 1.5 mg/dl. Creatinine clear ance was 45.8ml/min. His serum and spinal fluid lactate value were elevated. Biopsied musle showed an absence of ragged-red fibers, and the presence of an A-to-G point mutation at nucleotide pani 3243 in the mitochondrial tRNA^Leu(UUR) in peripheral blood leucocytes. He was thought to have MELAS. On the renal biopsy specimens, light microscopic examinations showed minor glomerular abnormalities with two glomerular collapses and tubulo-interstitial damage. Electron microscopic examinations showed partial thickening of the glomerular basement membrane. We report here this rare case of MELAS with renal disease, and also review seventeen cases of mitochondrial encephalopathy associ ated with renal disease. The existence of a relationship between mitochondrial disorder and renal damage remains obscure.

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