N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP) is an endogenous peptide that has been confirmed to show excellent organ‐protective effects. Even though originally discovered as a modulator of ...hemotopoietic stem cells, during the recent two decades, AcSDKP has been recognized as valuable antifibrotic peptide. The antifibrotic mechanism of AcSDKP is not yet clear; we have established that AcSDKP could target endothelial–mesenchymal transition program through the induction of the endothelial fibroblast growth factor receptor signaling pathway. Also, recent reports suggested the clinical significance of AcSDKP. The aim of this review was to update recent advances of the mechanistic action of AcSDKP and discuss translational research aspects.
N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (AcSDKP) is an endogenous peptide that has been confirmed to show excellent organ‐protective effects. The antifibrotic mechanism of AcSDKP is not yet clear, we have established that AcSDKP could target endothelial mesenchymal transition program through the induction of the endothelial fibroblast growth factor receptor signaling pathway. Also, recent reports suggested the clinical significance of AcSDKP.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell ...types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.
Kidney disease in diabetes is an important research topic in both clinical and basic science. Genetic analysis provides key translational data. In this regard, Jiang et al. emphasize some potential ...concerns over and problems with former genetics analysis methods, especially in common disease conditions such as kidney disease in diabetic patients.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inhibitors of sodium–glucose cotransporter 2 (SGLT2) have undoubtedly shifted the paradigm for diabetes medicine and research and, especially, diabetic kidney disease (DKD). The pharmacological ...action of SGLT2 inhibitors is simply the release of glucose into urine; however, precisely how SGLT2 inhibitors contribute to the health of those with diabetes has still not been completely elucidated. Towards this end, the present review provides a novel insight into the action of SGLT2 inhibitors by highlighting a neglected fuel-burning system found in proximal tubular cells—‘glycolysis’. In addition, exploring the details of the molecular mechanisms and clinical biomarkers of the organ protection conferred by SGLT2 inhibitors is now required to prepare for the next stage of clinical diabetes medicine—the ‘post-SGLT2 inhibitor era’.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
All types of progressive chronic kidney disease (CKD) inevitably induce renal fibrosis, the hallmark of which is the activation and accumulation of a large number of matrix-producing fibroblasts or ...myofibroblasts. The activated fibroblasts or myofibroblasts are derived from diverse origins, such as residential fibroblasts, vascular pericytes, epithelial-to-mesenchymal transition (EMT), and bone marrow (circulating fibrocytes). Recently, endothelial-to-mesenchymal transition (EndMT) or endothelial-to-myofibroblast transition has also been suggested to promote fibrosis and is recognized as a novel mechanism for the generation of myofibroblasts. Similar to EMT, during EndMT, endothelial cells lose their adhesion and apical–basal polarity to form highly invasive, migratory, spindle-shaped, elongated mesenchymal cells. More importantly, biochemical changes accompany these distinct changes in cell polarity and morphology, including the decreased expression of endothelial markers and the acquisition of mesenchymal markers. This review highlights evidence supporting the important role of EndMT in the development of renal fibrosis in CKD and its underlying mechanisms, including novel biological significance of microRNA regulation.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Due to the spread of the western style diet, which is characterized by high intake of processed food, micronutrients (vitamins and minerals) deficiency is increasing in the Japanese population of all ...ages and genders. During pregnancy, the elevated demand for micronutrients put pregnant women at even higher risk of micronutrients deficiency. Some micronutrients are relatively famous such that women with reproductive age are recommended to take folic acid supplementation for the prevention of neural tube defect. However, it is not generally known that folate is also important for fetal growth throughout the pregnancy course and for prevention of pregnancy complications, and that pregnant women should continue to take supplementation during pregnancy and lactation. The types of micronutrients and the duration of supplementation are both important factors to maintain normal pregnancies. This review focused on four micronutrients that are commonly deficient in Japanese pregnant women, folate, vitamin B12, vitamin D, calcium, and magnesium. The detrimental effects of homocysteine accumulation associated with the above micronutrient defects and its link to catechol‐o‐methyltransferase insufficiency are described. We also discussed possible molecular mechanisms of pregnancy complications and the development origin of health and disease (DOHaD) regarding micronutrient deficiencies from the point of view of one carbon metabolism.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged ...as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2-induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.
Aims/Introduction
Tubulointerstitial fibrosis is a hallmark of diabetic nephropathy and is associated with an epithelial‐to‐mesenchymal transition (EMT) program and aberrant glycolysis. Dimeric ...pyruvate kinase (PK) M2 (PKM2) acts as a key protein kinase in aberrant glycolysis by promoting the accumulation of hypoxia‐inducible factor (HIF)‐1α, while tetrameric PKM2 functions as a pyruvate kinase in oxidative phosphorylation. The aim of the research is to study the effect of PKM2 tetramer activation on preventing kidney fibrosis via suppression of aberrant glycolysis and the EMT program.
Materials and methods
In vivo: Streptozotocin (STZ) was utilized to induce diabetes in 8‐week‐old CD‐1 mice; 4 weeks after diabetes induction, proteinuria‐induced kidney fibrosis was developed by intraperitoneal injection of bovine serum albumin (BSA: 0.3 g/30 g BW) for 14 days; The PKM2 activator TEPP‐46 was also administered orally simultaneously. In vitro: HK2 cells were co‐treated with high‐glucose media or/and TGF‐β1 and TEPP46 for 48 h, cellular protein was extracted for evaluation.
Results
Diabetic mice developed kidney fibrosis associated with aberrant glycolysis and EMT; BSA injection accelerated kidney fibrosis in both the control and diabetic mice; TEPP‐46 rescued the kidney fibrosis. In HK2 cells, TEPP‐46 suppressed the EMT program induced by TGF‐β1 and/or high‐glucose incubation. TEPP‐46‐induced PKM2 tetramer formation and PK activity resulted in suppression of HIF‐1α and lactate accumulation. Specific siRNA‐mediated knockdown of HIF‐1α expression diminished high glucose‐induced mesenchymal protein levels.
Conclusion
PKM2 activation could restore the tubular phenotype via suppression of the EMT program and aberrant glycolysis, providing an alternative target to mitigate fibrosis in diabetic kidneys.
Diabetic kidney disease displayed kidney fibrosis associated with aberrant glycolysis and EMT program, these alterations were related to the increased level of dimeric‐PKM2 formation, PKM2 activation by TEPP46 rescued the kidney fibrosis by promoting PKM2 tetramer formation, and inhibiting dimeric‐PKM2 which directly interacted with HIF‐1α and promoted its transcription.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Obesity is an epidemic problem in the world and is associated with several health problems, including diabetes, cardiovascular disease, respiratory failure, muscle weakness, and cancer. The precise ...molecular mechanisms by which obesity induces these health problems are not yet clear. To better understand the pathomechanisms of human disease, good animal models are essential. In this paper, we will analyze animal models of obesity and their use in the research of obesity-associated human health conditions and diseases such as diabetes, cancer, and obstructive sleep apnea syndrome.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
PDF
