Although histone acetylation, an epigenetic modification, has been reported to be related to the progression of various diseases, its involvement in nephrosclerosis is unclear. Dahl salt-sensitive rats were used as a model of nephrosclerosis in this study. The rats were divided into three groups: (i) normal-salt diet group, (ii) high-salt diet group (HS), and (iii) HS administered daily with curcumin, a histone acetyltransferase inhibitor (HS+C). At 6 weeks after the treatment, the kidneys were dissected. Morphologic changes were assessed by Masson's trichrome staining. The number of macrophages, fibroblasts and the cells expressing acetylated histone H3 at Lys 9 (H3K9) were assessed by immunohistochemistry. Although both HS and HS+C rats revealed a marked increase in systolic blood pressure, serum creatinine was increased only in HS rats at 6 weeks. In the HS rats, nephrosclerosis was induced, accompanying a significant accumulation of macrophages and fibroblasts. The inflammation and fibrosis was markedly suppressed in the HS+C group. The level of histone acetylation at Lys 9 was enhanced in the HS rats, whereas curcumin administration suppressed the histone acetylation. Moreover, in the HS rats, interleukin-6 gene expression was associated with acetylated H3K9, as revealed by chromatin immunoprecipitation assay. Our results suggested that curcumin ameliorates nephrosclerosis via suppression of histone acetylation, independently of hypertension.
Summary: A 36-year-old woman diagnosed with Silver-Russell syndrome during childhood presented to our department after a primary care physician suspected renal dysfunction. At birth, she had an extremely low weight (1210 g), and in childhood, she was diagnosed with Silver-Russell syndrome. At the age of 14 she was found to have proteinuria; however, the condition was never further examined. One month prior to her presentation to our department, the following were noted: 3+ urinary protein, 3.9 urinary protein/creatinine ratio, and 48 mL/min/1.73 m2 estimated glomerular filtration rate. Abdominal computed tomography revealed small kidneys difficult to visualize using ultrasound. Therefore, an open renal biopsy was performed. The renal biopsy revealed no significant findings in the glomerulus except glomerular hypertrophy, and the glomerular density in the cortical area was low (0.6/mm2). The patient was diagnosed with oligomeganephronia. Proteinuria and renal dysfunction were likely due to glomerular hyperfiltration resulting from a low nephron count caused by low birth weight. Silver-Russell syndrome is characterized by intrauterine growth retardation and additional developmental disorders after birth. Here, we detected oligomeganephronia following kidney biopsy in a patient with Silver-Russell syndrome. We suspect that a reduced number of nephrons due to low birth weight caused proteinuria and renal dysfunction.
Abstract Background and Aims We presented previously that Am80, a synthetic retinoic acid receptor α specific agonist, inhibited the expression of Krüppel-like transcription factor 5 (KLF5) and reduced peritoneal fibrosis in mice. Now, we examined further detail about the mechanism to inhibit peritoneal fibrosis. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. After 3 weeks of treatment, peritoneal tissues were examined using serial sections by immunohistochemistry to identify what kind of cells expressed KLF5. We also examined the effect of Am80 to inhibit peritoneal fibrosis in vitro. Results While KLF5 was expressed in the thickened submesothelial area of CG injected mice, Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening. The numbers of transforming growth factor β positive cells, α-smooth muscle actin (αSMA) or F4/80 positive cells were significantly decreased in Am80 treated group. KLF5 was expressed in αSMA, F4/80 or CD31 positive cells. Conclusion These results indicate the KLF5 might not only associate phenotypical differentiation from fibroblasts to myofibroblasts but also regulate inflammatory responses and angiogenesis in peritoneal fibrosis model. Am80 can suppress peritoneal fibrosis through inhibiting these mechanisms. In vitro experiments are ongoing.
Protein S (PS) deficiency, which is caused by various factors including congenital and acquired disorders, is a risk factor for thrombophilia. We described 3 patients with different backgrounds, who all exhibited PS deficiency. The first patient was a 47-year-old woman who suffered from frequent cerebral infarctions, deep-vein thrombosis (DVT) of her lower extremities, and pulmonary thromboembolism. Her son suffered from skin necrosis due to PS deficiency and both had the same mutant allele of the PS gene. The second patient was a 50-year-old woman who experienced a cold sensation in her fingers. Her relatives had a history of cerebrovascular disease. No mutation was detected in her PS gene. The third patient was a 27-year-old man with antiphospholipid antibody. He suffered from thrombocytopenia, skin necrosis, DVT of his lower extremities, and pulmonary thromboembolism. A mutation was identified in the steroid hormone-binding globulin-like (SHBG) domain of his PS gene. Neither his parents nor siblings had a history of thrombosis. The mutations found in the first and third patients were both missense mutations in the SHBG domain that have not been reported previously. The third patient had a mutation in the site that is involved in binding to C4b-binding protein, which modifies the immune response. These three cases provide key insights into the pathophysiology of PS deficiency.
A 66-year-old male presented with renal dysfunction. At the time of presentation, his serum creatinine (sCr) was 2.55 mg/dL, estimated glomerular filtration rate (eGFR) was 20.93 ml/min/1.73 m2, urinary red blood cell (RBC) was 30-49/high power field, and urine protein-creatinine ratio was 0.43 g/gCr. The patient had no urinalysis abnormalities or renal dysfunction within the year prior to presentation but had gross hematuria after the third and fourth coronavirus disease 2019 (COVID-19) vaccinations. Therefore, immunoglobulin A nephropathy (IgAN) was suspected and a percutaneous renal biopsy was performed. Renal pathology confirmed IgAN and interstitial nephritis and glucocorticoid therapy was initiated. Glucocorticoids improved renal function, and microscopic hematuria resolved. Although previous reports have shown that the COVID-19 vaccine induces various renal diseases, complications associated with these two renal diseases are rare. In this case, while IgAN was suspected based on episodes of gross hematuria after vaccination, renal biopsy confirmed it and also revealed interstitial nephritis.
