Yoichiro Ikeda - Academia.edu (original) (raw)
Papers by Yoichiro Ikeda
Journal of the American Society of Nephrology : JASN, 2018
After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblast... more After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets ; however, protocols for transduction of kidney mesenchymal cells have not been established. We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids. Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by...
Journal of Atherosclerosis and Thrombosis, 2018
Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined b... more Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. aHUS is caused by uncontrolled complement activation in the alternative pathway (AP). A variety of genetic defects in complement-related factors or acquired autoantibodies to the complement regulators have been found in 50 to 60% of all cases. Recently, however, the classification and diagnosis of aHUS are becoming more complicated. One reason for this is that some factors, which have not been regarded as complement-related factors, have been reported as predisposing factors for phenotypic aHUS. Given that genotype is highly correlated with the phenotype of aHUS, careful analysis of underlying genetic abnormalities or acquired factors is needed to predict the prognosis or to decide an optimal treatment for the disease. Another reason is that complement dysregulation in the AP have also been found in a part of other types of TMA such as transplantation-related TMA and pregnancy-related complication. Based on these findings, it is now time to redefine aHUS according to the genetic or acquired background of abnormalities. Here, we review the pathogeneses and the corresponding phenotypes of aHUS and complement-related TMAs. aosylceramide on target cell surface and leads to cytotoxicity including protein synthesis and apoptosis, and also induces the secretion of unusually large VWF multimers from endothelial cells 4). Historically, the term "atypical HUS (aHUS)" was used to describe HUS not caused by the infection of STEC. Therefore, a category of aHUS included not only complement-related TMA, but also TMAs caused by various factors, such as drug, malignancy, pregnancy, transplantation, etc. However, since 1980s, various clinical and experimental studies have shown that 50% to 60% cases of aHUS arise from inherited and/or acquired complement abnormalities in the alternative pathway (AP). According to these progresses, the term "aHUS" came to be used to only describe complement-mediated aHUS and was distinguished from TMAs with coexisting disease or triggers, which were named "secondary TMA" in the criteria of Japan 5, 6). The classification of aHUS and secondary TMA, however, remains controversial. More
Internal Medicine
An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and th... more An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and the most likely cause detected during a workup was monoclonal IgG-λ in the urine and serum. Predominant IgG and λ light chain deposition was confirmed only by immunofluorescence using formalin-fixed, paraffin-embedded tissue and not by immunohistochemistry. A smaller and non-linear dynamic range of immunohistochemistry makes it less quantitative than immunofluorescence staining and may explain why immunohistochemistry failed to detect the light chain restriction. This case suggests that immunohistochemistry may not serve as a substitute for immunofluorescence on formalin-fixed, paraffin-embedded tissue in detecting masked monoclonal immunoglobulin deposits, although further research is warranted.
Histology and histopathology, 2015
The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide arr... more The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide array of biologic processes including embryonic development, branching morphogenesis, proliferation and carcinogenesis. Over the past ten years it has become increasingly clear that Wnt signaling also regulates the response of adult organs to disease processes, including kidney disease. This review will focus on the growing literature implicating important roles for Wnt signaling during disease in two separate kidney compartments: the tubular epithelium and the interstitium.
Journal of Clinical Investigation, 2015
Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scarsecreti... more Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scarsecreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1 + myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.
Journal of Rare Diseases Research & Treatment, 2018
Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by the dysfunction of the alte... more Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by the dysfunction of the alternative pathway of the complement system, which leads to the spontaneous activation of the complement system in the circulating plasma or cell surface. Recently our group published the cohort analysis of aHUS in Japan (n=118). Through the study, we revealed the followings; 1) the genetic background of aHUS in Japan was different from that in Western countries, 2) the most frequent genetic mutation detected in this study was I1157T in C3 (n=24), which was associated with superior renal outcome in spite of frequent replases, 3) Anti-CFH antibody positive aHUS had an excellent renal outcome, 4) 44% cases presented nephrotic syndrome, 5) only 12 % developed end stage renal disease (ESRD) and 6) there were 13 cases that discontinued eculizumab treatment and were followed up. These findings might help establishing the robust evidence for the optimal treatment of aHUS.
Nihon Jinzo Gakkai shi, 2007
A case of de novo focal segmental glomerulosclerosis occurred one and half years after kidney tra... more A case of de novo focal segmental glomerulosclerosis occurred one and half years after kidney transplantation supposed to be caused by calcineurin inhibitor.
The American Journal of Pathology, 2011
Although kidney functions deteriorate with age, little is known about the general morphological a... more Although kidney functions deteriorate with age, little is known about the general morphological alterations and mechanisms of renal senescence. We hypothesized that carbonyl stress causes senescence and investigated the possible role of glyoxalase I (GLO1), which detoxifies precursors of advanced glycation end products in the aging process of the kidney. We observed amelioration of senescence in GLO1-transgenic aged rats (assessed by expression levels of senescence markers such as p53, p21(WAF1/CIP1), and p16(INK4A)) and a positive rate of senescence-associated β-galactosidase (SABG) staining, associated with reduction of renal advanced glycation end product accumulation (estimated by the amount of carboxyethyl lysine). GLO1-transgenic rats showed amelioration of interstitial thickening (observed as an age-related presentation in human renal biopsy specimens) and were protected against age-dependent decline of renal functions. We used GLO1 overexpression or knockdown in primary renal proximal tubular epithelial cells to investigate the effect of GLO1 on cellular senescence. Senescence markers were significantly up-regulated in renal proximal tubular epithelial cells at late passage and in those treated with etoposide, a chemical inducer of senescence. GLO1 cellular overexpression ameliorated and knockdown enhanced the cellular senescence phenotypes. Furthermore, we confirmed the association of decreased GLO1 enzymatic activity and age-dependent deterioration of renal function in aged humans with GLO1 mutation. These findings indicate that GLO1 ameliorates carbonyl stress to retard renal senescence.
Journal of Clinical Investigation, 2015
Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secret... more Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.
Journal of the American Society of Nephrology : JASN, 2018
After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblast... more After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets ; however, protocols for transduction of kidney mesenchymal cells have not been established. We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids. Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by...
Journal of Atherosclerosis and Thrombosis, 2018
Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined b... more Atypical hemolytic uremic syndrome (aHUS) is a type of thrombotic microangiopathy (TMA) defined by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. aHUS is caused by uncontrolled complement activation in the alternative pathway (AP). A variety of genetic defects in complement-related factors or acquired autoantibodies to the complement regulators have been found in 50 to 60% of all cases. Recently, however, the classification and diagnosis of aHUS are becoming more complicated. One reason for this is that some factors, which have not been regarded as complement-related factors, have been reported as predisposing factors for phenotypic aHUS. Given that genotype is highly correlated with the phenotype of aHUS, careful analysis of underlying genetic abnormalities or acquired factors is needed to predict the prognosis or to decide an optimal treatment for the disease. Another reason is that complement dysregulation in the AP have also been found in a part of other types of TMA such as transplantation-related TMA and pregnancy-related complication. Based on these findings, it is now time to redefine aHUS according to the genetic or acquired background of abnormalities. Here, we review the pathogeneses and the corresponding phenotypes of aHUS and complement-related TMAs. aosylceramide on target cell surface and leads to cytotoxicity including protein synthesis and apoptosis, and also induces the secretion of unusually large VWF multimers from endothelial cells 4). Historically, the term "atypical HUS (aHUS)" was used to describe HUS not caused by the infection of STEC. Therefore, a category of aHUS included not only complement-related TMA, but also TMAs caused by various factors, such as drug, malignancy, pregnancy, transplantation, etc. However, since 1980s, various clinical and experimental studies have shown that 50% to 60% cases of aHUS arise from inherited and/or acquired complement abnormalities in the alternative pathway (AP). According to these progresses, the term "aHUS" came to be used to only describe complement-mediated aHUS and was distinguished from TMAs with coexisting disease or triggers, which were named "secondary TMA" in the criteria of Japan 5, 6). The classification of aHUS and secondary TMA, however, remains controversial. More
Internal Medicine
An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and th... more An 84-year-old man developed a membranoproliferative glomerulonephritis pattern of injury, and the most likely cause detected during a workup was monoclonal IgG-λ in the urine and serum. Predominant IgG and λ light chain deposition was confirmed only by immunofluorescence using formalin-fixed, paraffin-embedded tissue and not by immunohistochemistry. A smaller and non-linear dynamic range of immunohistochemistry makes it less quantitative than immunofluorescence staining and may explain why immunohistochemistry failed to detect the light chain restriction. This case suggests that immunohistochemistry may not serve as a substitute for immunofluorescence on formalin-fixed, paraffin-embedded tissue in detecting masked monoclonal immunoglobulin deposits, although further research is warranted.
Histology and histopathology, 2015
The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide arr... more The evolutionary conserved Wnt signaling transduction pathway plays essential roles in a wide array of biologic processes including embryonic development, branching morphogenesis, proliferation and carcinogenesis. Over the past ten years it has become increasingly clear that Wnt signaling also regulates the response of adult organs to disease processes, including kidney disease. This review will focus on the growing literature implicating important roles for Wnt signaling during disease in two separate kidney compartments: the tubular epithelium and the interstitium.
Journal of Clinical Investigation, 2015
Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scarsecreti... more Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scarsecreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1 + myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.
Journal of Rare Diseases Research & Treatment, 2018
Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by the dysfunction of the alte... more Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by the dysfunction of the alternative pathway of the complement system, which leads to the spontaneous activation of the complement system in the circulating plasma or cell surface. Recently our group published the cohort analysis of aHUS in Japan (n=118). Through the study, we revealed the followings; 1) the genetic background of aHUS in Japan was different from that in Western countries, 2) the most frequent genetic mutation detected in this study was I1157T in C3 (n=24), which was associated with superior renal outcome in spite of frequent replases, 3) Anti-CFH antibody positive aHUS had an excellent renal outcome, 4) 44% cases presented nephrotic syndrome, 5) only 12 % developed end stage renal disease (ESRD) and 6) there were 13 cases that discontinued eculizumab treatment and were followed up. These findings might help establishing the robust evidence for the optimal treatment of aHUS.
Nihon Jinzo Gakkai shi, 2007
A case of de novo focal segmental glomerulosclerosis occurred one and half years after kidney tra... more A case of de novo focal segmental glomerulosclerosis occurred one and half years after kidney transplantation supposed to be caused by calcineurin inhibitor.
The American Journal of Pathology, 2011
Although kidney functions deteriorate with age, little is known about the general morphological a... more Although kidney functions deteriorate with age, little is known about the general morphological alterations and mechanisms of renal senescence. We hypothesized that carbonyl stress causes senescence and investigated the possible role of glyoxalase I (GLO1), which detoxifies precursors of advanced glycation end products in the aging process of the kidney. We observed amelioration of senescence in GLO1-transgenic aged rats (assessed by expression levels of senescence markers such as p53, p21(WAF1/CIP1), and p16(INK4A)) and a positive rate of senescence-associated β-galactosidase (SABG) staining, associated with reduction of renal advanced glycation end product accumulation (estimated by the amount of carboxyethyl lysine). GLO1-transgenic rats showed amelioration of interstitial thickening (observed as an age-related presentation in human renal biopsy specimens) and were protected against age-dependent decline of renal functions. We used GLO1 overexpression or knockdown in primary renal proximal tubular epithelial cells to investigate the effect of GLO1 on cellular senescence. Senescence markers were significantly up-regulated in renal proximal tubular epithelial cells at late passage and in those treated with etoposide, a chemical inducer of senescence. GLO1 cellular overexpression ameliorated and knockdown enhanced the cellular senescence phenotypes. Furthermore, we confirmed the association of decreased GLO1 enzymatic activity and age-dependent deterioration of renal function in aged humans with GLO1 mutation. These findings indicate that GLO1 ameliorates carbonyl stress to retard renal senescence.
Journal of Clinical Investigation, 2015
Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secret... more Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.