Macrophage impairment produced by Fc receptor gamma deficiency plays a principal role in the development of lipoprotein glomerulopathy in concert with apoE abnormalities.

BACKGROUND: To obtain a clear understanding of the pathogenesis of lipoprotein glomerulopathy (LPG), we studied the role of the deficiency of Fc receptor gamma chain (FcRγ) for the development of LPG in concert with apolipoprotein E (apoE) abnormalities. METHODS: We generated apoE and FcRγ double-knockout (FcRγ/apoE-KO) mice, and subsequently introduced several kinds of human recombinant apoE genes. At 21 days after infection, the mice were sacrificed and histologically examined. Peritoneal macrophages were evaluated for their response to modified lipids. RESULTS: In the FcRγ/apoE-KO mice, the human apoE3-injected mice showed the most drastic LPG-like changes, as well as prominent hypertriglyceridemia. Meanwhile, relative to the human apoE3-injected mice, the FcRγ/apoE-KO mice showed greater lipoprotein deposition and less macrophage infiltration into the mesangial area. Moreover, the peritoneal macrophages in the apoE/FcRγ-KO mice were impaired in lipid uptake and secretion of the cytokines monocyte chemotactic protein-1 and regulated upon activation, normal T-cell expressed and secreted, after the uptake of oxidized low-density lipoprotein. CONCLUSIONS: These results suggest that the impairment of macrophage function resulting from FcRγ deficiency plays a principal role in the development of LPG in the presence of apoE abnormalities.

[Case of suspicious lansoprazole-associated collagenous colitis in ANCA-associated nephritis].

In January 2003, a 70-year-old female consulted a doctor for a fever of unknown origin. She had microscopic hematuria, proteinuria, BUN 41 mg/dL, Cr 2.1 mg/dL and MPO-ANCA 44 U/mL, and was suspected of having ANCA-associated nephritis. A renal biopsy was not conducted because the patient had just one kidney. She was treated with prednisolone (PSL ; 40 mg/day). Subsequently, because of Cr level improvement, the amount of PSL was decreased. In October 2006, the patient again had microscopic hematuria, proteinuria and a slightly elevated Cr level. Lowering of BP and dehydration caused by a common cold were considered to be the cause of her renal dysfunction. She was admitted to Fukuoka University Hospital for 2 weeks, where she received diet therapy and a changed medication schedule in which furosemide was stopped and the dose of enalapril was decreased from 5 mg/day to 2.5 mg/day. Because the MPO-ANCA level was < 10 EU, the amount of PSL was not changed. After 11 months, treatment with lansoprazole at 30 mg/day was started. At the end of the same month, however, she exhibited gait disturbance due to swelling, redness and tenderness in the bilateral pedal joints. After one month of receiving lansoprazole, she experienced a high fever and an elevated Cr level. Accordingly she was again admitted to the hospital, where she was diagnosed with venous thrombosis in the lower limbs, and warfarization was begun. Her condition improved, gradually, and she was discharged from the hospital. After the discharge, she began to exhibit watery diarrhea three to four times per day. Therefore, treatment with warfarin potassium was stopped 50 days after it was begun. In spite of the cessation of warfarization, the diarrhea continued. She underwent bacterial culturing and lower endoscopic examinations (no biopsy was done), which showed erosion of the colon, but the cause of the diarrhea was not found. After 181 days of treatment with lansoprazole, administration of this drug was stopped. The symptoms disappeared within 5 days. There have been few reports of collagenous colitis with chronic diarrhea, but a good prognosis has been described in these cases. Clinicians should consider drug treatment as a possible cause of collagenous colitis in the case of patients with chronic diarrhea of unknown origin during the administration of medication.

Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice.

OBJECTIVE: A mutant of apolipoproteinE (apoE), ApoE-Sendai (Arg145Pro), is one of the major causative factors of human lipoprotein glomerulopathy (LPG). An apoE-deficient mouse with introduced ApoE-Sendai gene (ApoE-Sendai mouse) developed a murine counterpart of LPG, whereas it was also reported that apoE-deficient mouse (apoE KO mouse) spontaneously developed LPG-like lesion regardless of introduction of ApoE-Sendai gene. In the present study, we differentiated renal lesions between these two models by detailed analyses of histology and lipoprotein profile, and clarified the role of apoE variants. METHOD: ApoE-Sendai mice were induced by injection of adenovirus vectors. The kidneys showing LPG-like lesions in apoE-Sendai and apoE KO mice were histopathologically evaluated. Plasma lipids and lipoproteins of both mice were also examined. RESULTS: Histological alteration of the kidney in ApoE-Sendai mice was observed with light microscopy (in 40 out of 50 mice; mild 24, moderate 13, severe 3). Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG. Similar changes were found in hematoxylin-eosin stained sections of aged apoE KO mice. Meanwhile, periodic acid-Schiff, Azan Mallory, and Oil red O/Sudan III stained sections revealed that the dilated lumens of ApoE-Sendai mice mainly contained lipids and lipoproteins but those of aged apoE KO mice contained much other materials, e.g., proteins and fibrils. These findings were supported by electron micrographs, in which round-shaped droplets indicating lipoproteins were observed in ApoE-Sendai mice but not in aged apoE KO mice. In the kidney of apoE KO mice many anti-mouse CD68 Ab positive cells were detected. This contrasts with the result seen in ApoE-Sendai mice. The plasma lipoprotein compositions of the two types of mice were totally different. CONCLUSION: It was certain that the kidneys of aged apoE KO mice showed morphological alteration, but the histological findings of glomerular lesions were different from those seen in the kidneys of ApoE-Sendai mice. According to the histological findings and plasma lipoprotein profile, ApoE-Sendai mice, not apoE KO mice, is a murine model for human LPG. This means that apoE variants are essential to LPG.

Amelioration of diabetic nephropathy in OLETF rats by prostaglandin I(2) analog, beraprost sodium.

BACKGROUND: Strict control of blood glucose and blood pressure levels sometimes fails to delay the development of diabetic nephropathy, and an effective therapy is not yet available. The present study aimed to examine whether the prostaglandin I(2) analog beraprost sodium (BPS) ameliorates diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rat. METHOD: Fifty-week-old OLETF rats were divided into three groups according to treatment; 400 microg/kg body weight (BW) BPS, 200 microg/kg BW BPS, and 0.9% saline administration. Kidney histology, index of glomerulosclerosis, and glomerular volume were determined, and urine and serum chemistry were assessed. RESULTS: The values for urine protein excretion and serum blood urea nitrogen in BPS-treated rats were significantly lower than those in untreated rats. In rats treated with 400 microg/kg BW BPS, neither sclerotic changes nor inflammatory cell infiltration were observed. Index of glomerulosclerosis and glomerular volume were also significantly reduced compared with untreated rats. Intriguingly, BPS reduced the level of serum triglyceride. In the glomerulus of treated rats, advanced glycation end product formation and macrophage influx were suppressed in a dose-dependent manner. CONCLUSION: These findings indicate that BPS has a therapeutic effect on diabetic nephropathy in the OLETF rat, which suggests a potential application of this drug in the treatment of human diabetic nephropathy.