Fructose in the kidney: from physiology to pathology

The Warburg effect is a unique property of cancer cells, in which glycolysis is activated instead of mitochondrial respiration despite oxygen availability. However, recent studies found that the Warburg effect also mediates non-cancer disorders, including kidney disease. Currently, diabetes or glucose has been postulated to mediate the Warburg effect in the kidney, but it is of importance that the Warburg effect can be induced under nondiabetic conditions. Fructose is endogenously produced in several organs, including the kidney, under both physiological and pathological conditions. In the kidney, fructose is predominantly metabolized in the proximal tubules; under normal physiologic conditions, fructose is utilized as a substrate for gluconeogenesis and contributes to maintain systemic glucose concentration under starvation conditions. However, when present in excess, fructose likely becomes deleterious, possibly due in part to excessive uric acid, which is a by-product of fructose metabolism. A potential mechanism is that uric acid suppresses aconitase in the Krebs cycle and therefore reduces mitochondrial oxidation. Consequently, fructose favors glycolysis over mitochondrial respiration, a process that is similar to the Warburg effect in cancer cells. Activation of glycolysis also links to several side pathways, including the pentose phosphate pathway, hexosamine pathway, and lipid synthesis, to provide biosynthetic precursors as fuel for renal inflammation and fibrosis. We now hypothesize that fructose could be the mediator for the Warburg effect in the kidney and a potential mechanism for chronic kidney disease

The Impact of Fructose on Renal Function and Blood Pressure

Fructose is a sugar present in sucrose, high-fructose corn syrup, honey, and fruits. Fructose intake has increased markedly in the last two centuries, primarily due to increased intake of added sugars. Increasing evidence suggests that the excessive intake of fructose may induce fatty liver, insulin resistance, dyslipidemia, hypertension, and kidney disease. These studies suggest that excessive intake of fructose might have an etiologic role in the epidemic of obesity, diabetes, and cardiorenal disease

Bilateral herpes simplex keratitis in a patient with chronic graft-versus-host disease

Takahiko Hayashi1, Misaki Ishioka2, Norihiko Ito1, Yoko Kato1, Hisashi Nakagawa3, Hiroshi Hatano4, Nobuhisa Mizuki11Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan; 2Ryogoku Eye Clinic, Tokyo, Japan; 3Tokushima Eye Clinic, Higashimurayama-shi, Tokyo, Japan; 4Lumine Hatano Eye Clinic, Fujisawa, Fujisawa-shi, Kanagawa, JapanPurpose: To describe a case of bilateral herpes simplex keratitis accompanying chronic graft-versus-host disease (GVHD).Design: Observational case report.Case report: An 11-year-old boy with myelocytic leukemia underwent allogeneic bone marrow transplantation. He developed symptoms of the skin, eyes, and mouth, and lip biopsy indicated chronic GVHD. Persistent keratitis with corneal filaments and neovascularization was noted in both eyes. Sodium hyaluronate, autoserum, and 0.1% fluorometholone eyedrops were instilled for approximately 2 years to treat this keratitis, and there were no other ocular changes. Bilateral herpes simplex keratitis developed with geographic ulcers after topical betamethasone therapy, but responded to acyclovir ointment.Conclusions: Herpes keratitis should be considered in the differential diagnosis of bilateral keratitis in patients with reduced immunocompetence. During the course of chronic GVHD, corneal herpes may occur, so ocular treatment with topical corticosteroids should be managed by an ophthalmologist to monitor sight-threatening conditions such as corneal herpes.Keywords: chronic graft-versus-host disease, bone marrow transplant, corneal herpes, bilateral herpes simplex keratitis, dry eye

Angiotensinogen expression in neonates

Background We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin-angiotensin system (RAS) status during kidney development. Methods We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and one year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. Results Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased one year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and one year later were inversely correlated with estimated glomerular filtration rate one year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. Conclusions Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero

MYCL promotes iPSC-like colony formation via MYC Box 0 and 2 domains

iPS細胞作製過程における初期化因子MYCLのタンパク質ドメインの機能解析. 京都大学プレスリリース. 2021-12-20.Protein domain structures affect the quality of stem cells. 京都大学プレスリリース. 2021-12-20.Human induced pluripotent stem cells (hiPSCs) can differentiate into cells of the three germ layers and are promising cell sources for regenerative medicine therapies. However, current protocols generate hiPSCs with low efficiency, and the generated iPSCs have variable differentiation capacity among different clones. Our previous study reported that MYC proteins (c-MYC and MYCL) are essential for reprogramming and germline transmission but that MYCL can generate hiPSC colonies more efficiently than c-MYC. The molecular underpinnings for the different reprogramming efficiencies between c-MYC and MYCL, however, are unknown. In this study, we found that MYC Box 0 (MB0) and MB2, two functional domains conserved in the MYC protein family, contribute to the phenotypic differences and promote hiPSC generation in MYCL-induced reprogramming. Proteome analyses suggested that in MYCL-induced reprogramming, cell adhesion-related cytoskeletal proteins are regulated by the MB0 domain, while the MB2 domain regulates RNA processes. These findings provide a molecular explanation for why MYCL has higher reprogramming efficiency than c-MYC

Complete remission of diabetes with a transient HDAC inhibitor and insulin in streptozotocin mice

Despite the growing epidemic worldwide, diabetes is an incurable disease. We have been focusing on why diabetes manifests refractoriness to any therapy. We recently found that abnormal bone marrow-derived cells (BMDCs), namely, Vcam-1+ST-HSCs, was a key mechanism for diabetic complications. We then hypothesize that those aberrant BMDCs sustainedly impair pancreatic β cells. Here we show that eliminating abnormal BMDCs using bone marrow transplantation results in controlling serum glucose in diabetic mice, in which normoglycemia is sustained even after cessation of insulin therapy. Alternatively, abnormal BMDCs exhibiting epigenetic alterations are treated with an HDAC inhibitor, givinostat, in diabetic mice. As a result, those mice are normoglycemic along with restored insulin secretion even following the cessation of both insulin and givinostat. Diabetic cell fusion between abnormal BMDCs and resident cells is significantly blocked by the combination therapy in the pancreatic islets and thymus while surgical ablation of the thymus completely eliminates therapeutic protection in diabetic mice. In conclusion, diabetes is an epigenetic stem cell disorder with thymic disturbances. The combination may be applied to patients aiming at complete remission from diabetes in clinical medicine.journal articl

Association between haemoglobin concentration and intradialytic hypotension in patients undergoing maintenance haemodialysis: a retrospective cohort study

Objectives: Haemoglobin concentration is a potentially modifiable factor that may help lower the risk of intradialytic hypotension (IDH), but its association with IDH is not well understood. This study aimed to clarify the relationship between haemoglobin concentration and IDH.Design:Retrospective cohort study.Setting:We evaluated patients undergoing maintenance haemodialysis in December 2017 at Rakuwakai Otowa Kinen Hospital.Participants: A total of 543 patients were included. We defined exposure according to the following five categories depending on haemoglobin concentrations by 1.0 increments: <9.0, ≥9.0 to <10.0, 10.0 to <11.0, ≥11.0 to <12.0 and ≥12.0 g/dL.Primary outcome measure:The primary outcome of interest was the development of IDH, defined as any nadir <100 mm Hg if the pre-dialysis systolic blood pressure (SBP) was ≥160 mm Hg or any nadir <90 mm Hg if the pre-dialysis SBP was <160 mm Hg (IDHnadir).Results:Overall, IDHnadir occurred in 14.3% (465/3250) of the sessions. With a haemoglobin concentration of ≥10.0 to <11.0 g/dL set as reference, the adjusted ORs for IDHnadir were 0.82 (95% CI, 0.32 to 2.15), 1.16 (95% CI, 0.56 to 2.39), 1.26 (95% CI, 0.68 to 2.36) and 3.01 (95% CI, 1.50 to 6.07) for haemoglobin concentrations of <9.0, ≥9.0 to <10.0, ≥11.0 to <12.0 and ≥12.0 g/dL, respectively. In the cubic spline analysis, a high haemoglobin concentration was associated with the development of IDHnadir.Conclusion:High haemoglobin concentration is associated with IDH, and thus, the upper limit of haemoglobin concentration should be closely monitored in patients with IDH

Urinary angiotensinogen during renal development in neonates

Background All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates, and examined the relationship between urinary angiotensinogen levels and gestational age. Methods Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. Results Plasma angiotensinogen concentrations were not increased in preterm neonates compared to that in full-term neonates (P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared to that in full-term neonates (P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age (P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age (P = 0.7814). Conclusions These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development