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Zhang D, Zhang YH, Liu B, Yang HX, Li GT, Zhou HL, Wang YS. Role of peroxisomes in the pathogenesis and therapy of renal fibrosis. Metabolism 2025; 166:156173. [PMID: 39993498 DOI: 10.1016/j.metabol.2025.156173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 02/26/2025]
Abstract
Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.
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Affiliation(s)
- Dan Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Yang-He Zhang
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China
| | - Hong-Xia Yang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Guang-Tao Li
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
| | - Hong-Lan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun 130021, China.
| | - Yi-Shu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China.
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Lin ZM, Gao HY, Shi SH, Li YT. Mizagliflozin ameliorates diabetes induced kidney injury by inhibitor inhibit inflammation and oxidative stress. World J Diabetes 2025; 16:92711. [PMID: 39817219 PMCID: PMC11718448 DOI: 10.4239/wjd.v16.i1.92711] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 04/26/2024] [Accepted: 10/08/2024] [Indexed: 11/29/2024] Open
Abstract
BACKGROUND Mizagliflozin (MIZ) is a specific inhibitor of sodium-glucose cotransport protein 1 (SGLT1) originally developed as a medication for diabetes. AIM To explore the impact of MIZ on diabetic nephropathy (DN). METHODS Diabetic mice were created using db/db mice. They were administered either a low dose (0.5 mg/kg) or a high dose (1.0 mg/kg) of the SGLT1 inhibitor MIZ via stomach gavage for 8 weeks. Subsequently, mesangial cells (MCs) were isolated and subjected to high glucose conditions in culture to assess the effects of MIZ on DN. RESULTS The results showed that low doses of MIZ significantly reduced albuminuria to a level comparable to that achieved with high doses in db/db mice. High doses of MIZ led to a substantial increase in body weight in mice, along with decreased blood glucose levels and food intake. Moreover, the intervention with high-dose MIZ notably decreased the expression of extracellular matrix genes, such as collagen type 1 alpha 1 mRNA levels. While the expression of SGLT1 increased after exposure to high glucose, it decreased following treatment with MIZ. Furthermore, MIZ intervention was more effective in improving lactate dehydrogenase levels in MCs induced by high glucose compared to canagliflozin. MIZ also significantly elevated levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione, while reducing malondialdehyde levels. CONCLUSION These findings indicate that MIZ can ameliorate DN by inhibiting SGLT1, inflammation, and oxidative stress.
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Affiliation(s)
- Zhi-Min Lin
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Han-Yuan Gao
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Shu-Han Shi
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
| | - Yue-Ting Li
- Department of Nephrology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, Fujian Province, China
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Hsu YC, Shih YH, Ho C, Liu CC, Liaw CC, Lin HY, Lin CL. Ethyl Acetate Fractions of Salvia miltiorrhiza Bunge (Danshen) Crude Extract Modulate Fibrotic Signals to Ameliorate Diabetic Kidney Injury. Int J Mol Sci 2024; 25:8986. [PMID: 39201671 PMCID: PMC11354680 DOI: 10.3390/ijms25168986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/30/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Diabetic nephropathy, a leading cause of end-stage renal disease, accounts for significant morbidity and mortality. It is characterized by microinflammation in the glomeruli and myofibroblast activation in the tubulointerstitium. Salvia miltiorrhiza Bunge, a traditional Chinese medicine, is shown to possess anti-inflammatory and anti-fibrotic properties, implying its renal-protective potential. This study investigates which type of component can reduce the damage caused by diabetic nephropathy in a single setting. The ethyl acetate (EtOAc) layer was demonstrated to provoke peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ activities in renal mesangial cells by dual luciferase reporter assay. In a high glucose (HG)-cultured mesangial cell model, the EtOAc layer substantially inhibited HG-induced elevations of interleukin-1β, transforming growth factor-β1 (TGF-β1), and fibronectin, whereas down-regulated PPAR-γ was restored. In addition, among the extracts of S. miltiorrhiza, the EtOAc layer effectively mitigated TGF-β1-stimulated myofibroblast activation. The EtOAc layer also showed a potent ability to attenuate renal hypertrophy, proteinuria, and fibrotic severity by repressing diabetes-induced proinflammatory factor, extracellular matrix accumulation, and PPAR-γ reduction in the STZ-induced diabetes mouse model. Our findings, both in vitro and in vivo, indicate the potential of the EtOAc layer from S. miltiorrhiza for future drug development targeting diabetic nephropathy.
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Affiliation(s)
- Yung-Chien Hsu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan
| | - Ya-Hsueh Shih
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
| | - Cheng Ho
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Cheng-Chi Liu
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
| | - Chia-Ching Liaw
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112304, Taiwan;
| | - Hui-Yi Lin
- School of Pharmacy, China Medical University, Taichung 406040, Taiwan
| | - Chun-Liang Lin
- Departments of Nephrology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan; (Y.-C.H.); (Y.-H.S.); (C.-C.L.)
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 61363, Taiwan;
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 10507, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
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Anegawa T, Sasaki KI, Ishizaki Y, Negoto S, Oryoji A, Nakamura E, Otsuka H, Hiromatsu S, Fukumoto Y, Tayama E. Effects of Pemafibrate on Reducing Oxidative Stress and Augmenting Angiogenesis in Ischemic Limb Tissue. Kurume Med J 2024; 69:167-174. [PMID: 38233183 DOI: 10.2739/kurumemedj.ms6934006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
OBJECTIVE Oxidative damage is observed in the ischemic limbs of patients with arteriosclerosis obliterans. We investigated whether pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced oxidative stress in ischemic limbs and consequently rescued limb damage in model mice. MATERIALS AND METHODS We surgically induced hind-limb ischemia in mice and orally administered pemafibrate solution (P-05 group, 0.5 mg/kg/day; P-10 group, 1.0 mg/kg/day) or control solution (control group). Seven days after the surgery, differences in reactive oxygen species (ROS) contents, antioxidative enzyme and transcription factor expression, blood flow, and capillary density in ischemic limbs were assessed. RESULTS Tissue ROS levels were lower in the P-05 and P-10 groups compared with those in the control group. Although the tissue expression levels of nuclear factor-erythroid 2-related factor 2 increased in the P-10 group compared with that in the control group, no corresponding changes were observed in the tissue expression of four antioxidative enzymes. The limb salvage rates and capillary densities in ischemic limbs were higher in the P-05 and P-10 groups than that in the control group. CONCLUSION Pemafibrate treatment reduced oxidative stress and augmented angiogenesis in ischemic limbs, contributing to prevention of limb damage in mice.
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Affiliation(s)
- Tomoyuki Anegawa
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Ken-Ichiro Sasaki
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
| | - Yuta Ishizaki
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
| | - Shinya Negoto
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Atsunobu Oryoji
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Eiji Nakamura
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Hiroyuki Otsuka
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Shinichi Hiromatsu
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
| | - Yoshihiro Fukumoto
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine
| | - Eiki Tayama
- Division of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine
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Izumihara R, Nomoto H, Kito K, Yamauchi Y, Omori K, Shibayama Y, Yanagiya S, Miya A, Kameda H, Cho KY, Nagai S, Sakuma I, Nakamura A, Atsumi T, on Behalf of the PARM-T2D Study Group. Switching from Conventional Fibrates to Pemafibrate Has Beneficial Effects on the Renal Function of Diabetic Subjects with Chronic Kidney Disease. Diabetes Metab J 2024; 48:473-481. [PMID: 38419467 PMCID: PMC11140405 DOI: 10.4093/dmj.2023.0370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 11/22/2023] [Indexed: 03/02/2024] Open
Abstract
BACKGRUOUND Fibrates have renal toxicity limiting their use in subjects with chronic kidney disease (CKD). However, pemafibrate has fewer toxic effects on renal function. In the present analysis, we evaluated the effects of pemafibrate on the renal function of diabetic subjects with or without CKD in a real-world clinical setting. METHODS We performed a sub-analysis of data collected during a multi-center, prospective, observational study of the effects of pemafibrate on lipid metabolism in subjects with type 2 diabetes mellitus complicated by hypertriglyceridemia (the PARM-T2D study). The participants were allocated to add pemafibrate to their existing regimen (ADD-ON), switch from their existing fibrate to pemafibrate (SWITCH), or continue conventional therapy (CTRL). The changes in estimated glomerular filtration rate (eGFR) over 52 weeks were compared among these groups as well as among subgroups created according to CKD status. RESULTS Data for 520 participants (ADD-ON, n=166; SWITCH, n=96; CTRL, n=258) were analyzed. Of them, 56.7% had CKD. The eGFR increased only in the SWITCH group, and this trend was also present in the CKD subgroup (P<0.001). On the other hand, eGFR was not affected by switching in participants with severe renal dysfunction (G3b or G4) and/or macroalbuminuria. Multivariate analysis showed that being older and a switch from fenofibrate were associated with elevation in eGFR (both P<0.05). CONCLUSION A switch to pemafibrate may be associated with an elevation in eGFR, but to a lesser extent in patients with poor renal function.
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Affiliation(s)
- Rimi Izumihara
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroshi Nomoto
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kenichi Kito
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yuki Yamauchi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kazuno Omori
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Yui Shibayama
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shingo Yanagiya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Aika Miya
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - So Nagai
- Division of Diabetes and Endocrinology, Department of Medicine, NTT Sapporo Medical Center, Sapporo, Japan
| | - Ichiro Sakuma
- Caress Sapporo Hokko Memorial Clinic, Sapporo, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - on Behalf of the PARM-T2D Study Group
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Division of Diabetes and Endocrinology, Department of Medicine, NTT Sapporo Medical Center, Sapporo, Japan
- Caress Sapporo Hokko Memorial Clinic, Sapporo, Japan
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Tan E, Gao Z, Wang Q, Han B, Shi H, Wang L, Zhu G, Hou Y. Berberine ameliorates renal interstitial inflammation and fibrosis in mice with unilateral ureteral obstruction. Basic Clin Pharmacol Toxicol 2023; 133:757-769. [PMID: 37811696 DOI: 10.1111/bcpt.13947] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 07/26/2023] [Accepted: 08/01/2023] [Indexed: 10/10/2023]
Abstract
Berberine acts via multiple pathways to alleviate fibrosis in various tissues and shows renoprotective effects. However, its role and underlying mechanisms in renal fibrosis remain unclear. Herein, we aimed to investigate the protective effects and molecular mechanisms of berberine against unilateral ureteric obstruction-induced renal fibrosis. The results indicated that berberine treatment (50 mg/kg/day) markedly alleviated histopathological alterations, collagen deposition and inflammatory cell infiltration in kidney tissue and restored mouse renal function. Mechanistically, berberine intervention inhibited NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and the levels of the inflammatory cytokine IL-1β in the kidneys of unilateral ureteric obstruction mice. In addition, berberine relieved unilateral ureteric obstruction-induced renal injury by activating adenosine monophosphate-activated protein kinase (AMPK) signalling and promoting fatty acid β-oxidation. In vitro models showed that berberine treatment prevented the TGF-β1-induced profibrotic phenotype of hexokinase 2 (HK-2) cells, characterized by loss of an epithelial phenotype (alpha smooth muscle actin [α-SMA]) and acquisition of mesenchymal marker expression (E-cadherin), by restoring abnormal fatty acid β-oxidation and upregulating the expression of the fatty acid β-oxidation related-key enzymes or regulators (phosphorylated-AMPK, peroxisome proliferator activated receptor alpha [PPARα] and carnitine palmitoyltransferase 1A [CPT1A]). Collectively, berberine alleviated renal fibrosis by inhibiting NLRP3 inflammasome activation and protected tubular epithelial cells by reversing defective fatty acid β-oxidation. Our findings might be exploited clinically to provide a potential novel therapeutic strategy for renal fibrosis.
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Affiliation(s)
- Enxue Tan
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Zhihong Gao
- Department of Nephrology, Shanxi Bethune Hospital, Taiyuan, China
| | - Qian Wang
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Baosheng Han
- Department of Cardiac Surgery, Shanxi Cardiovascular Hospital, Taiyuan, China
| | - Honghong Shi
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Lihua Wang
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Guozhen Zhu
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Yanjuan Hou
- Department of Nephrology, Second Hospital, Shanxi Medical University, Taiyuan, China
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Kitamura S, Murao N, Yokota S, Shimizu M, Ono T, Seino Y, Suzuki A, Maejima Y, Shimomura K. Effect of fenofibrate and selective PPARα modulator (SPPARMα), pemafibrate on KATP channel activity and insulin secretion. BMC Res Notes 2023; 16:202. [PMID: 37697384 PMCID: PMC10494450 DOI: 10.1186/s13104-023-06489-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023] Open
Abstract
OBJECTIVE Insulin secretion is regulated by ATP-sensitive potassium (KATP) channels in pancreatic beta-cells. Peroxisome proliferator-activated receptors (PPAR) α ligands are clinically used to treat dyslipidemia. A PPARα ligand, fenofibrate, and PPARγ ligands troglitazone and 15-deoxy-∆12,14-prostaglandin J2 are known to close KATP channels and induce insulin secretion. The recently developed PPARα ligand, pemafibrate, became a new entry for treating dyslipidemia. Because pemafibrate is reported to improve glucose intolerance in mice treated with a high fat diet and a novel selective PPARα modulator, it may affect KATP channels or insulin secretion. RESULTS The effect of fenofibrate (100 µM) and pemafibrate (100 µM) on insulin secretion from MIN6 cells was measured by using batch incubation for 10 and 60 min in low (2 mM) and high (10 mM) glucose conditions. The application of fenofibrate for 10 min significantly increased insulin secretion in low glucose conditions. Pemafibrate failed to increase insulin secretion in all of the conditions experimented in this study. The KATP channel activity was measured by using whole-cell patch clamp technique. Although fenofibrate (100 µM) reduced the KATP channel current, the same concentration of pemafibrate had no effect. Both fenofibrate and pemafibrate had no effect on insulin mRNA expression.
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Affiliation(s)
- Shigeki Kitamura
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
- Department of Plastic and Reconstructive Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Naoya Murao
- Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, Toyoake, Japan
| | - Shoko Yokota
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
| | - Masaru Shimizu
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
- Department of Neurology, Matsumura General Hospital, Iwaki, Japan
| | - Tomoyuki Ono
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
| | - Yusuke Seino
- Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, Toyoake, Japan
| | - Atsushi Suzuki
- Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, Toyoake, Japan
| | - Yuko Maejima
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
| | - Kenju Shimomura
- Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295 Japan
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Njeim R, Alkhansa S, Fornoni A. Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease. Pharmaceutics 2023; 15:pharmaceutics15051360. [PMID: 37242602 DOI: 10.3390/pharmaceutics15051360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.
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Affiliation(s)
- Rachel Njeim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
- AUB Diabetes, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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Seki M, Nakano T, Tanaka S, Matsukuma Y, Funakoshi K, Ohkuma T, Kitazono T. Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD). Clin Exp Nephrol 2023; 27:358-364. [PMID: 36738362 DOI: 10.1007/s10157-023-02322-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/21/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. METHODS The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20 years and over, who have received the care of a nephrologist or a diabetologist for more than 3 months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15 g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150 mg/dL and < 1,000 mg/dL) at allocation. In the treatment group, pemafibrate is added to conventional treatment, while conventional treatment is continued with no additional treatment in the control group. Target patient enrollment is 140 patients. The primary endpoint is the change from baseline in the logarithmic urine protein/creatinine ratio at 12 months after study start. CONCLUSION This study will provide new findings on the renal protective effect of pemafibrate in CKD patients. CLINICAL TRIAL REGISTRATION This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN-CTR: UMIN000042284).
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Affiliation(s)
- Mai Seki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Shigeru Tanaka
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yuta Matsukuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Kouta Funakoshi
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Toshiaki Ohkuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
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10
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Horinouchi Y, Murashima Y, Yamada Y, Yoshioka S, Fukushima K, Kure T, Sasaki N, Imanishi M, Fujino H, Tsuchiya K, Shinomiya K, Ikeda Y. Pemafibrate inhibited renal dysfunction and fibrosis in a mouse model of adenine-induced chronic kidney disease. Life Sci 2023; 321:121590. [PMID: 36940907 DOI: 10.1016/j.lfs.2023.121590] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 03/23/2023]
Abstract
AIMS Peroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile. MAIN METHODS The risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice). KEY FINDINGS The ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1β) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1β, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice. SIGNIFICANCE These results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders.
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Affiliation(s)
- Yuya Horinouchi
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Yuka Murashima
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Yuto Yamada
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Shun Yoshioka
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Keijo Fukushima
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
| | - Takumi Kure
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Naofumi Sasaki
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Masaki Imanishi
- Department of Medical Pharmacology, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
| | - Hiromichi Fujino
- Department of Pharmacology for Life Sciences, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
| | - Koichiro Tsuchiya
- Department of Medical Pharmacology, Graduate School of Pharmaceutical Sciences & Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.
| | - Kazuaki Shinomiya
- Department of Pharmaceutical Care and Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan.
| | - Yasumasa Ikeda
- Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
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11
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Effect of Pemafibrate on Hemorheology in Patients with Hypertriglyceridemia and Aggravated Blood Fluidity Associated with Type 2 Diabetes or Metabolic Syndrome. J Clin Med 2023; 12:jcm12041481. [PMID: 36836015 PMCID: PMC9962113 DOI: 10.3390/jcm12041481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Persistent high serum triglyceride (TG) and free fatty acid (FFA) levels, which are common in metabolic syndrome and type 2 diabetes, are risk factors for cardiovascular events because of exacerbated hemorheology. To explore the effects of pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, on hemorheology, we performed a single-center, nonrandomized, controlled study in patients with type 2 diabetes (HbA1c 6-10%) or metabolic syndrome, with fasting TG levels of ≥ 150 mg/dL and a whole blood transit time of > 45 s on a microarray channel flow analyzer (MCFAN). Patients were divided into a study group, receiving 0.2 mg/day of pemafibrate (n = 50) for 16 weeks, and a non-pemafibrate control group (n = 46). Blood samples were drawn 8 and 16 weeks after entry to the study to evaluate whole blood transit time as a hemorheological parameter, leukocyte activity by MCFAN, and serum FFA levels. No serious adverse events were observed in either of the groups. After 16 weeks, the pemafibrate group showed a 38.6% reduction in triglycerides and a 50.7% reduction in remnant lipoproteins. Pemafibrate treatment did not significantly improve whole blood rheology or leukocyte activity in patients with type 2 diabetes mellitus or metabolic syndrome complicated by hypertriglyceridemia and exacerbated hemorheology.
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12
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Zambon A, Averna M, D'Erasmo L, Arca M, Catapano A. New and Emerging Therapies for Dyslipidemia. Endocrinol Metab Clin North Am 2022; 51:635-653. [PMID: 35963633 DOI: 10.1016/j.ecl.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) continues to represent a growing global health challenge. Despite guideline-recommended treatment of ASCVD risk, including antihypertensive, high-intensity statin therapy, and antiaggregant agents, high-risk patients, especially those with established ASCVD and patients with type 2 diabetes, continue to experience cardiovascular events. Recent years have brought significant developments in lipid and atherosclerosis research. Several lipid drugs owe their existence, in part, to human genetic evidence. Here, the authors briefly review the mechanisms, the effect on lipid parameters, and safety profiles of some of the most promising new lipid-lowering approaches that will be soon available in our daily clinical practice.
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Affiliation(s)
- Alberto Zambon
- University of Padova, Clinica Medica 1, Department of Medicine - DIMED, Via Giustiniani 2, Padova 35128, Italy.
| | - Maurizio Averna
- Policlinico, Paolo Giaccone, Via del Vespro 149, Palermo 90127, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, University of Rome, Viale dell' Università 37, Sapienza 00161, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, University of Rome, Viale dell' Università 37, Sapienza 00161, Italy
| | - Alberico Catapano
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via G. Balzaretti 9, Milan 20133, Italy; IRCCS MultiMedica, Via Milanese 300, Sesto San Giovanni (MI) 200099, Italy
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13
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Liu Y, Zhu R, Liu B, Wang W, Yang P, Cao Z, Yang X, Du W, Yang Q, Liang J, Hu J, Ma G. Antidiabetic Effect of Rehmanniae Radix Based on Regulation of TRPV1 and SCD1. Front Pharmacol 2022; 13:875014. [PMID: 35694255 PMCID: PMC9178243 DOI: 10.3389/fphar.2022.875014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: This study aimed to disclose the antidiabetic mechanisms of Rehmanniae Radix (RR). Methods: The antidiabetic effect of RR was studied in Streptozocin (STZ)-induced diabetes mellitus (DM) rats and HepG2 cells with insulin resistance (IR). Antidiabetic targets and signaling pathways of RR were confirmed by the network pharmacology and transcriptome analysis as well as HK2 cells induced by high glucose (HG). Results: After the DM rats were administrated RR extract (RRE) for 4 weeks, their body weight was 10.70 ± 2.00% higher than those in the model group, and the fasting blood glucose (FBG), AUC of the oral glucose tolerance test, and insulin sensitivity test values were 73.23 ± 3.33%, 12.31 ± 2.29%, and 13.61 ± 5.60% lower in the RRE group, respectively. When compared with the model group, an increase of 45.76 ± 3.03% in the glucose uptake of HepG2 cells with IR was seen in the RRE group. The drug (RR)-components-disease (DM)-targets network with 18 components and 58 targets was established. 331 differentially expressed genes (DEGs) were identified. TRPV1 and SCD1 were important DEGs by the intersectional analysis of network pharmacology and renal transcriptome. The TRPV1 overexpression significantly inhibited apoptosis and oxidative stress of the HK2 cells induced by HG, while SCD1 overexpression induced apoptosis and oxidative stress of the HK2 cells induced by low and high glucose. When compared to the HG group, the mRNA and protein expressions of TRPV1 in the presence of RRE (100 μg/ml) increased by 3.94 ± 0.08 and 2.83 ± 0.40 folds, respectively. Conclusion: In summary, RR displayed an inspiring antidiabetic effect by reducing FBG and IR, upregulating the mRNA and protein expressions of TRPV1, and downregulating mRNA expression of SCD1. Induction of TRPV1 and inhibition of SCD1 by RR was possibly one of its antidiabetic mechanisms.
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Affiliation(s)
- Ye Liu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Ruizheng Zhu
- Department of Dermatology, Minhang Hospital, Fudan University, Shanghai, China
| | - Bei Liu
- School of Pharmacy, Fudan University, Shanghai, China
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wuqing Wang
- Department of Dermatology, Minhang Hospital, Fudan University, Shanghai, China
| | - Ping Yang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Zhonglian Cao
- School of Pharmacy, Fudan University, Shanghai, China
| | - Xiaolei Yang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Wandi Du
- School of Pharmacy, Fudan University, Shanghai, China
| | - Qing Yang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Jingru Liang
- School of Pharmacy, Fudan University, Shanghai, China
| | - Jiarong Hu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Guo Ma
- School of Pharmacy, Fudan University, Shanghai, China
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14
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Association between Pemafibrate Therapy and Triglyceride to HDL-Cholesterol Ratio. J Clin Med 2022; 11:jcm11102820. [PMID: 35628945 PMCID: PMC9148088 DOI: 10.3390/jcm11102820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 04/10/2022] [Accepted: 05/15/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Pemafibrate is a novel selective peroxisome proliferator-activated receptor-α modulator, which was demonstrated to reduce serum triglyceride level with few drug-related adverse events in phase II and III clinical trials. However, its clinical implication in real-world practice remains unknown. Triglyceride/HDL-cholesterol ratio is a surrogate of small dense LDL-cholesterol, which is a newly proposed cardiovascular risk factor independent of LDL-cholesterol levels. Methods: Consecutive patients who received pemafibrate between April 2020 and September 2021 and continued therapy for at least 3 months were included in this retrospective analysis. The primary outcome was the trend in triglyceride/HDL-cholesterol ratio during the 3-month treatment period. The change in cardiovascular event rate between the one-year pre-treatment period and the on-treatment period was also analyzed. Results: A total of 19 patients (median age 63 years, 74% men) were included and continued pemafibrate therapy for 3 months without any drug-related adverse events. Sixteen were add-on and three were conversions from other fibrates. Triglyceride/HDL-cholesterol ratio decreased significantly from 5.85 (4.19, 16.1) to 3.14 (2.39, 4.62) (p < 0.001). The cardiovascular event rate decreased significantly from 0.632 events/year to 0.080 events/year (p < 0.001). Conclusions: Pemafibrate therapy might have the potential to lower triglyceride/HDL-cholesterol ratio and decrease cardiovascular events.
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15
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Goujon M, Woszczyk J, Gaudelot K, Swierczewski T, Fellah S, Gibier JB, Van Seuningen I, Larrue R, Cauffiez C, Gnemmi V, Aubert S, Pottier N, Perrais M. A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma. Cancers (Basel) 2022; 14:cancers14030795. [PMID: 35159062 PMCID: PMC8834244 DOI: 10.3390/cancers14030795] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 02/04/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.
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Affiliation(s)
- Marine Goujon
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Justine Woszczyk
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Kelly Gaudelot
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Thomas Swierczewski
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Sandy Fellah
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Jean-Baptiste Gibier
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- CHU Lille, Service d’Anatomo-Pathologie, F-59000 Lille, France
| | - Isabelle Van Seuningen
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Romain Larrue
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- CHU Lille, Service de Toxicologie et Génopathies, F-59000 Lille, France
| | - Christelle Cauffiez
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
| | - Viviane Gnemmi
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- CHU Lille, Service d’Anatomo-Pathologie, F-59000 Lille, France
| | - Sébastien Aubert
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- CHU Lille, Service d’Anatomo-Pathologie, F-59000 Lille, France
| | - Nicolas Pottier
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- CHU Lille, Service de Toxicologie et Génopathies, F-59000 Lille, France
| | - Michaël Perrais
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France; (M.G.); (J.W.); (K.G.); (T.S.); (S.F.); (J.-B.G.); (I.V.S.); (R.L.); (C.C.); (V.G.); (S.A.); (N.P.)
- Correspondence: ; Tel.: +33-3-20-29-88-62
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16
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Martin WP, Chuah YHD, Abdelaal M, Pedersen A, Malmodin D, Abrahamsson S, Hutter M, Godson C, Brennan EP, Fändriks L, le Roux CW, Docherty NG. Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 12:757228. [PMID: 35222262 PMCID: PMC8867227 DOI: 10.3389/fendo.2021.757228] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/23/2021] [Indexed: 01/03/2023] Open
Abstract
Background Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. Methods The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (1H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. Results RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Conclusions Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.
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Affiliation(s)
- William P. Martin
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Yeong H. D. Chuah
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Mahmoud Abdelaal
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Anders Pedersen
- Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden
| | - Daniel Malmodin
- Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden
| | - Sanna Abrahamsson
- Bioinformatics Core Facility, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michaela Hutter
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Eoin P. Brennan
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Lars Fändriks
- Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carel W. le Roux
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
- Diabetes Research Group, Ulster University, Coleraine, United Kingdom
| | - Neil G. Docherty
- Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
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Theofilis P, Vordoni A, Koukoulaki M, Vlachopanos G, Kalaitzidis RG. Dyslipidemia in Chronic Kidney Disease: Contemporary Concepts and Future Therapeutic Perspectives. Am J Nephrol 2021; 52:693-701. [PMID: 34569479 DOI: 10.1159/000518456] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/12/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is an increasingly prevalent disease state met with great morbidity and mortality primarily resulting from the high incidence of adverse cardiovascular outcomes. Therapeutic strategies in this patient population aim at controlling modifiable cardiovascular risk factors, including dyslipidemia. SUMMARY In this review article, we first provide the latest pathophysiologic evidence regarding the altered dyslipidemia pattern in CKD, followed by its contemporary management according to the latest guidelines. Moreover, we present the current progress regarding the emerging therapeutic strategies. Key Messages: The presence of renal impairment leads to alterations in cholesterol structure, metabolism, and reverse transport paired with increased oxidative stress. Statins remain the cornerstone of dyslipidemia management in patients with kidney dysfunction who are at risk for cardiovascular events. However, their efficacy is debatable in end-stage renal disease under renal replacement therapy. Therefore, novel treatment approaches aiming at hypertriglyceridemia, proprotein convertase subtilisin/kexin type 9, and lipoprotein(a) are under rigorous investigation while the research of gut microbiome might provide additional mechanistic and therapeutic insight.
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Affiliation(s)
| | - Aikaterini Vordoni
- Department of Nephrology, General Hospital of Nikaia-Piraeus, Athens, Greece
| | - Maria Koukoulaki
- Department of Nephrology, General Hospital of Nikaia-Piraeus, Athens, Greece
| | | | - Rigas G Kalaitzidis
- Department of Nephrology, General Hospital of Nikaia-Piraeus, Athens, Greece
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Aomura D, Harada M, Yamada Y, Nakajima T, Hashimoto K, Tanaka N, Kamijo Y. Pemafibrate Protects against Fatty Acid-Induced Nephropathy by Maintaining Renal Fatty Acid Metabolism. Metabolites 2021; 11:372. [PMID: 34207854 PMCID: PMC8230306 DOI: 10.3390/metabo11060372] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/25/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.
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Affiliation(s)
- Daiki Aomura
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (D.A.); (M.H.); (Y.Y.); (K.H.)
| | - Makoto Harada
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (D.A.); (M.H.); (Y.Y.); (K.H.)
| | - Yosuke Yamada
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (D.A.); (M.H.); (Y.Y.); (K.H.)
| | - Takero Nakajima
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (T.N.); (N.T.)
| | - Koji Hashimoto
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (D.A.); (M.H.); (Y.Y.); (K.H.)
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (T.N.); (N.T.)
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan
| | - Yuji Kamijo
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; (D.A.); (M.H.); (Y.Y.); (K.H.)
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19
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Yokote K, Yamashita S, Arai H, Araki E, Matsushita M, Nojima T, Suganami H, Ishibashi S. Effects of pemafibrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double-blind placebo-controlled clinical trials. Cardiovasc Diabetol 2021; 20:96. [PMID: 33947390 PMCID: PMC8097867 DOI: 10.1186/s12933-021-01291-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/27/2021] [Indexed: 12/26/2022] Open
Abstract
Background Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnormalities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. Methods We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo-controlled trials that examined the effects of daily pemafibrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafibrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. Results The study population was 1253 patients randomized to placebo (n = 298) or pemafibrate 0.1 mg/day (n = 127), 0.2 mg/day (n = 584), or 0.4 mg/day (n = 244). Participant mean age was 54.3 years, 65.4 % had BMI ≥ 25 kg/m2, 35.8 % had type 2 diabetes, and 42.6 % had fatty liver. Fasting glucose, fasting insulin, and HOMA-IR decreased significantly in all pemafibrate groups compared to placebo. The greatest decrease was for pemafibrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose − 0.25 mmol/L; fasting insulin − 3.31 µU/mL; HOMA-IR − 1.28. ALT, γ-GT, ALP, and total bilirubin decreased significantly at all pemafibrate doses vs. placebo, with the greatest decrease in the pemafibrate 0.4 mg/day group: LS mean change from baseline in ALT − 7.6 U/L; γ-GT − 37.3 U/L; ALP − 84.7 U/L; and total bilirubin − 2.27 µmol/L. Changes in HbA1c and AST did not differ significantly from placebo in any pemafibrate groups in the overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased significantly in all pemafibrate groups compared to placebo, with the greatest increase in the pemafibrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo. Conclusions In patients with hypertriglyceridemia, pemafibrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01291-w.
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Affiliation(s)
- Koutaro Yokote
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan. .,Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.
| | - Shizuya Yamashita
- Rinku General Medical Center, 2-23 Ohrai-kita, Rinku, Izumisano-shi, Osaka, 598-8577, Japan
| | - Hidenori Arai
- National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu-shi, Aichi, 474-8511, Japan
| | - Eiichi Araki
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi, Kumamoto, 860-8556, Japan
| | - Mitsunori Matsushita
- Medical Affairs Department, Kowa Company, Ltd, 3-4-14 Nihonbashi-honcho, Chuo-ku, Tokyo, 103-8433, Japan
| | - Toshiaki Nojima
- Clinical Data Science Department, Kowa Company, Ltd, 3-4-14 Nihonbashi-honcho, Chuo- ku, Tokyo, 103-8433, Japan
| | - Hideki Suganami
- Clinical Data Science Department, Kowa Company, Ltd, 3-4-14 Nihonbashi-honcho, Chuo- ku, Tokyo, 103-8433, Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan
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20
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Xie L, Guo K, Lu S, Wang N, Wang Y, Chen H, Liu J, Jia W. Diabetic nephropathy in mice is aggravated by the absence of podocyte IRE1 and is correlated with reduced kidney ADH1 expression. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:636. [PMID: 33987334 PMCID: PMC8106116 DOI: 10.21037/atm-20-6356] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Inositol-requiring enzyme 1 (IRE1) plays a critical role in attenuating endoplasmic reticulum (ER) stress associated with renal injury which may also be a factor in diabetic nephropathy (DN). Alcohol dehydrogenase type I (ADH1) activity is prominent in the kidney, ADH1 activity is also reported to exert protective effects against ER stress that are not caused by alcohol consumption. However, the role of IRE1 in DN and the correlation between IRE1 and ADH1 activity remain unclear. Methods IRE1α floxed mice (Ire1f/f ) of C57BL/6J background were established and crossbred with Ire1αf/f mice to produce podocyte-specific IRE1α knockout mice. Male db/db mice (C57BLKS/J-leprdb/leprdb mice) were used as a DN model. Male mice were made diabetic by injection of streptozotocin. pLKO.1-based vectors encoding short hairpin RNA (shRNA) specific to the IRE1α gene were transfected into HEK293T cells to knockdown IRE1α in mouse podocytes. ELISA, Masson's staining, and electron microscopy were performed to analyze the development of DN. The ADH1 expression was assayed by qPCR and western blot. Results We found that IRE activity was increased in the glomeruli of DN mouse models. In contrast, ADH1 expression was decreased in these models and mice with podocyte-specific disruption of IRE1 (PKO mice). PKO mice that were made diabetic using strepto-zotocin exhibited accelerated proteinuria, enhanced glomerular fibrosis, and podocyte cell death. In addition, in cultured podocytes, the knockdown of IRE1 downregulated the ADH1 mRNA expression and induced ER stress, consistent with the result of PKO mice, while its detrimental effects were reversed by ADH1 overexpression. Conclusions Activation of IRE1 in podocytes serves to limit the progress of DN. The dependence of kidney ADH1 expression on podocyte IRE1 further suggests that ADH1 activity may play an important role downstream of IRE1 in protecting against DN.
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Affiliation(s)
- Liping Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kaifeng Guo
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University.,Minhang Branch, Zhongshan Hospital, Fudan University, Central Hospital of Minhang District, Shanghai, China
| | - Sijia Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ning Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yanping Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haibing Chen
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junli Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiping Jia
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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21
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Suto K, Fukuda D, Shinohara M, Ganbaatar B, Yagi S, Kusunose K, Yamada H, Soeki T, Hirata KI, Sata M. Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice. J Atheroscler Thromb 2021; 28:1349-1360. [PMID: 33775978 PMCID: PMC8629704 DOI: 10.5551/jat.61101] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aims:
Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice.
Methods:
Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed.
Results:
Pemafibrate reduced both triglyceride and non-high-density lipoprotein-cholesterol levels (
P
＜0.01), without affecting body weight. It also decreased circulating levels of AA (
P
＜0.001), thromboxane B
2
(
P
＜0.001), prostaglandin E
2
, leukotriene B
4
(
P
＜0.05), and 5-hydroxyeicosatetraenoic acid (
P
＜0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ
12,14
-prostaglandin J
2
, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (
P
＜0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (
P
＜0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function.
Conclusion:
Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.
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Affiliation(s)
- Kumiko Suto
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Daiju Fukuda
- Department of Cardio-Diabetes Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Masakazu Shinohara
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine.,Division of Epidemiology, Kobe University Graduate School of Medicine
| | - Byambasuren Ganbaatar
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Shusuke Yagi
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Kenya Kusunose
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
| | - Hirotsugu Yamada
- Department of Community Medicine for Cardiology, Tokushima University Graduate School of Biomedical Sciences
| | - Takeshi Soeki
- Department of Community Medicine and Medical Science, Tokushima University Graduate School of Biomedical Sciences
| | - Ken-Ichi Hirata
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine
| | - Masataka Sata
- Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences
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22
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Fruchart JC, Hermans MP, Fruchart-Najib J. Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα): New Opportunities to Reduce Residual Cardiovascular Risk in Chronic Kidney Disease? Curr Atheroscler Rep 2020; 22:43. [PMID: 32671476 PMCID: PMC7363727 DOI: 10.1007/s11883-020-00860-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a common feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator-activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches. RECENT FINDINGS Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator-activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand's selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD. Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk.
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Affiliation(s)
- Jean-Charles Fruchart
- Residual Risk Reduction Initiative (R3i) Foundation, Picassoplatz 8, 4010, Basel, Switzerland.
| | - Michel P Hermans
- Division of Endocrinology and Nutrition, Cliniques Universitaires St-Luc and Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Jamila Fruchart-Najib
- Residual Risk Reduction Initiative (R3i) Foundation, Picassoplatz 8, 4010, Basel, Switzerland
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Abstract
PURPOSE OF REVIEW Metabolic reprogramming is a prominent feature of cyst epithelial cells in autosomal dominant polycystic kidney disease (ADPKD). Peroxisome proliferator activated receptor alpha (PPARα) is a transcription factor that regulates many aspects of cellular metabolism. The purpose of this review is to understand the role of PPARα in ADPKD. RECENT FINDINGS PPARα expression is reduced in ADPKD kidneys of mice and humans. This downregulation is in part secondary to microRNA mediated translational repression and leads to impairment of fatty acid metabolism. Genetic studies demonstrate that deletion of Pparα aggravates cyst growth in a slowly progressive mouse model of ADPKD. Recent studies also show that administration of Pparα agonists ameliorates cyst burden in mice. SUMMARY Abnormal reduction of PPARα affects cellular metabolism in ADPKD. Pparα is a modulator of cyst progression in mouse models of ADPKD. These studies establish PPARα as an exciting new drug target for the treatment of individuals with ADPKD.
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24
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Guo K, Pan P, Wu M, Ma Y, Lu J, Chen H. Hyposialylated angiopoietin-like-4 induces apoptosis of podocytes via β1 Integrin/FAK signaling in diabetic nephropathy. Mol Cell Endocrinol 2020; 505:110730. [PMID: 31981598 DOI: 10.1016/j.mce.2020.110730] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 01/18/2020] [Accepted: 01/20/2020] [Indexed: 12/12/2022]
Abstract
Angiopoietin-like-4 (ANGPTL4) is reported to mediate proteinuria in some types of glomerulonephropathy. However, the mechanism underlying the effect on podocytes of ANGPTL4 under pathologic conditions in diabetic nephropathy (DN) is unclear. We investigated the role of ANGPTL4 in the pathogenesis of DN. In DN rats, elevated ANGPTL4 expression was associated with increased proteinuria, glomerular hypertrophy, and ultrastructural changes in podocytes. In vitro, hyperglycemia induced the upregulation of ANGPTL4, which led to activation of integrin-β1/FAK signaling with increased apoptosis of podocytes and actin cytoskeleton derangement. These pathological changes were reversed by transfection with a lentivirus expressing short hairpin RNA against integrin-β1 or an ANGPTL4-neutralizing antibody in vitro. Furthermore, supplementation with the sialic acid precursor ManNAc reversed these pathological changes and conferred renoprotection in a mouse model of DN. Our findings suggest that ANGPTL4 mediates high glucose-induced loss of podocytes by modulating their detachment and apoptosis in vivo and in vitro. This study deepens our understanding of the mechanisms of podocyte loss in DN and shows targeting ANGPTL4-related signaling has therapeutic potential for DN.
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Affiliation(s)
- Kaifeng Guo
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China; Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University; Minhang Branch, Zhongshan Hospital, Fudan University; Central Hospital of Minhang District, Shanghai, 201199, China
| | - Pan Pan
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Mian Wu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Yiwen Ma
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Junxi Lu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Haibing Chen
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a New Selective PPARα Modulator: Drug Concept and Its Clinical Applications for Dyslipidemia and Metabolic Diseases. Curr Atheroscler Rep 2020; 22:5. [PMID: 31974794 PMCID: PMC6978439 DOI: 10.1007/s11883-020-0823-5] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
PURPOSE OF REVIEW Reduction of serum low-density lipoprotein cholesterol (LDL-C) levels by statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has been shown to significantly reduce cardiovascular events risk. However, fasting and postprandial hypertriglyceridemia as well as reduced high-density lipoprotein cholesterol (HDL-C) remain as residual risk factors of atherosclerotic cardiovascular diseases (ASCVD). To treat patients with hypertriglyceridemia and/or low HDL-C, drugs such as fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids have been used. However, fibrates were demonstrated to cause side effects such as liver dysfunction and increase in creatinine levels, and thus large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. The failure could be attributed to their low selectivity and potency for binding to peroxisome proliferator-activated receptor (PPAR) α. To resolve these issues, the concept of selective PPARα modulator (SPPARMα) with a superior balance of efficacy and safety has been proposed and pemafibrate (K-877) has been developed. RECENT FINDINGS Pemafibrate, one of SPPARMsα, was synthesized by Kowa Company, Ltd. for better efficiency and safety. Clinical trials in Japan have established the superiority of pemafibrate on effects on serum triglycerides (TG) reduction and HDL-C elevation as well safety. Although available fibrates showed worsening of liver and kidney function test values, pemafibrate indicated improved liver function test values and was less likely to increase serum creatinine or decrease estimated glomerular filtration rate (eGFR). Very few drug-drug interactions were observed even when used concomitantly with statins. Furthermore, pemafibrate is metabolized in the liver and excreted into the bile, while many of available fibrates are mainly excreted from the kidney. Therefore, pemafibrate can be used safely even in patients with impaired renal function since there is no significant increase in its blood concentration. A large-scale trial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes is ongoing. Pemafibrate is one of novel SPPARMsα and has superior benefit-risk balance compared to conventional fibrates and can be applicable for patients for whom the usage of existing fibrates is difficult such as those who are taking statins or patients with renal dysfunction. In the current review, all the recent data on pemafibrate will be summarized.
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Affiliation(s)
- Shizuya Yamashita
- Department of Cardiology, Rinku General Medical Center, Izumisano, Osaka, 598-8577, Japan.
| | - Daisaku Masuda
- Department of Cardiology, Rinku General Medical Center, Izumisano, Osaka, 598-8577, Japan
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26
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Effect of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator (SPPARMα), on urinary protein excretion in IgA nephropathy with hypertriglyceridemia. CEN Case Rep 2020; 9:141-146. [PMID: 31950425 DOI: 10.1007/s13730-020-00444-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 12/28/2019] [Indexed: 02/01/2023] Open
Abstract
Lipid abnormalities, including hypertriglyceridemia, are one of the most common comorbidities in patients with chronic kidney disease (CKD) and are independently associated with disease progression. However, it remains uncertain whether treatment for hypertriglyceridemia has favorable effects on the clinical course of IgA nephropathy (IgAN). Pemafibrate is a novel selective peroxisome proliferator-activated receptor-alpha modulator and may be distinct from conventional fibrates in terms of its pharmacological activity and hepatic and renal safety. A recent clinical study demonstrated that pemafibrate was safe and effective for correcting pro-atherogenic lipid abnormalities in CKD patients with a wide range of renal insufficiency. However, the effect of pemafibrate on renal function in patients with IgAN and hypertriglyceridemia has not been verified. This paper is the first to show that 12 months of pemafibrate (0.1 mg daily) administration in three drug-naïve and mild IgAN patients with variable renal dysfunction and histopathology proven IgAN decreased serum triglyceride level and excretion of urinary protein and liver-type fatty acid-binding protein with no change in estimated glomerular filtration rate (eGFR). These findings suggest that pemafibrate is safe and effective for correcting hypertriglyceridemia and decreasing urinary protein excretion without changing eGFR and blood pressure levels in mild IgAN patients with hypertriglyceridemia.
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27
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Abstract
PURPOSE OF REVIEW Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. RECENT FINDINGS The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. SUMMARY SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.
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Affiliation(s)
| | - Raul D Santos
- Hospital Israelita Albert Einstein
- Lipid Clinic, Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
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Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate. Int J Mol Sci 2019; 20:ijms20225682. [PMID: 31766193 PMCID: PMC6888257 DOI: 10.3390/ijms20225682] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/05/2019] [Accepted: 11/11/2019] [Indexed: 12/16/2022] Open
Abstract
Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.
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Fruchart JC, Santos RD, Aguilar-Salinas C, Aikawa M, Al Rasadi K, Amarenco P, Barter PJ, Ceska R, Corsini A, Després JP, Duriez P, Eckel RH, Ezhov MV, Farnier M, Ginsberg HN, Hermans MP, Ishibashi S, Karpe F, Kodama T, Koenig W, Krempf M, Lim S, Lorenzatti AJ, McPherson R, Nuñez-Cortes JM, Nordestgaard BG, Ogawa H, Packard CJ, Plutzky J, Ponte-Negretti CI, Pradhan A, Ray KK, Reiner Ž, Ridker PM, Ruscica M, Sadikot S, Shimano H, Sritara P, Stock JK, Su TC, Susekov AV, Tartar A, Taskinen MR, Tenenbaum A, Tokgözoğlu LS, Tomlinson B, Tybjærg-Hansen A, Valensi P, Vrablík M, Wahli W, Watts GF, Yamashita S, Yokote K, Zambon A, Libby P. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol 2019; 18:71. [PMID: 31164165 PMCID: PMC6549355 DOI: 10.1186/s12933-019-0864-7] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 04/29/2019] [Indexed: 12/12/2022] Open
Abstract
In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.
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Affiliation(s)
| | - Raul D. Santos
- Hospital Israelita Albert Einstein, and Lipid Clinic, Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil
| | - Carlos Aguilar-Salinas
- Unidad de Investigacion de Enfermedades Metabolicas, Department of Endocrinolgy and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Masanori Aikawa
- Center for Interdisciplinary Cardiovascular Sciences and Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine and Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Khalid Al Rasadi
- Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman
| | - Pierre Amarenco
- Department of Neurology and Stroke Center, Paris-Diderot-Sorbonne University, Paris, France
| | - Philip J. Barter
- Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW Australia
| | - Richard Ceska
- IIIrd Dept Int. Med, Center for Preventive Cardiology, 3rd Internal Medicine Clinic, University General Hospital and Charles University, Prague, Czech Republic
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Jean-Pierre Després
- Centre de recherche sur les soins et les services de première ligne-Université Laval du CIUSSS de la Capitale-Nationale, Department of Kinesiology, Faculty of Medicine, Université Laval, Québec, QC Canada
| | - Patrick Duriez
- INSERM, CHU Lille, U1171-Degenerative & Vascular Cognitive Disorders, University of Lille, Faculty of Pharmacy, University of Lille, UDSL, Lille, France
| | - Robert H. Eckel
- Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO USA
| | - Marat V. Ezhov
- Laboratory of Lipid Disorders, National Cardiology Research Center, Moscow, Russian Federation
| | - Michel Farnier
- Lipid Clinic, Point Médical and Department of Cardiology, CHU Dijon-Bourgogne, Dijon, France
| | - Henry N. Ginsberg
- Columbia University Vagelos College of Physicians and Surgeons, New York, USA
| | - Michel P. Hermans
- Division of Endocrinology and Nutrition, Cliniques Universitaires St-Luc and Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Fredrik Karpe
- OCDEM, University of Oxford and the NIHR Oxford Biomedical Research Centre, OUH Foundation Trust, Churchill Hospital, Oxford, UK
| | - Tatsuhiko Kodama
- Laboratory for System Biology and Medicine Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universitat München, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Michel Krempf
- Mass Spectrometry Core facility of West Human Nutrition Research Center (CRNHO), Hotel Dieu Hospital, Nantes, France
- Inra, UMR 1280, Physiologie des Adaptations Nutritionnelles, Nantes, France
- Department of Endocrinology, Metabolic diseases and Nutrition, G and R Laennec Hospital, Nantes, France
| | - Soo Lim
- Department of Internal Medicine, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Alberto J. Lorenzatti
- DAMIC Medical Institute/Rusculleda Foundation for Research, Córdoba, Argentina
- Cardiology Department, Córdoba Hospital, Córdoba, Argentina
| | - Ruth McPherson
- Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada
| | - Jesus Millan Nuñez-Cortes
- Internal Medicine, Lipids Unit, Gregorio Marañón University Hospital, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigaciones Sanitarias Gregorio Marañón, Madrid, Spain
| | - Børge G. Nordestgaard
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hisao Ogawa
- National Cerebral and Cardiovascular Center, Suita, Osaka Japan
| | - Chris J. Packard
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Jorge Plutzky
- Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Carlos I. Ponte-Negretti
- Unidad de Prevención Cardiometabólica Cardiocob. Servicio de Cardiología Hospital el Pino Santiago de Chile, Sociedad Inter Americana de Cardiología SIAC Chairman Cardiovascular Prevention Comite, Santiago de Chile, Chile
| | - Aruna Pradhan
- Division of Cardiovascular Medicine, VA Boston Medical Center, Boston, MA USA
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Kausik K. Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London, UK
| | - Željko Reiner
- Department of Internal Medicine, University Hospital Centre Zagreb, School of Medicine, Zagreb University, Kispaticeva 12, Zagreb, Croatia
| | - Paul M. Ridker
- Division of Cardiovascular Medicine and Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università Degli Studi di Milano, Milan, Italy
| | - Shaukat Sadikot
- Department of Endocrinology/Diabetology, Jaslok Hospital and Research Centre, Mumbai, India
| | - Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575 Japan
| | - Piyamitr Sritara
- Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jane K. Stock
- R3i Foundation, Picassoplatz 8, 4010 Basel, Switzerland
| | - Ta-Chen Su
- Departments of Internal Medicine and Environmental and Occupational Medicine, National Taiwan University; Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
| | - Andrey V. Susekov
- Faculty of Clinical Pharmacology and Therapeutics, Academy for Postgraduate Continuous Medical Education, Moscow, Russian Federation
| | | | - Marja-Riitta Taskinen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki and Clinical Research Institute, HUCH Ltd., Helsinki, Finland
| | - Alexander Tenenbaum
- Sackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel
- Cardiac Rehabilitation Institute, Sheba Medical Center, 5265601 Tel Hashomer, Israel
| | - Lale S. Tokgözoğlu
- Department of Cardiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Brian Tomlinson
- Department of Medicine & Theraputics, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Rigshospitalet; Copenhagen University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Paul Valensi
- Department of Endocrinology, Diabetology and Nutrition, Jean-Verdier Hospital (AP-HP), Paris 13 University, Sorbonne Paris Cité, CRNH-IdF, CINFO, 93140 Bondy, France
| | - Michal Vrablík
- 3rd Department of Medicine, 1st Faculty of Medicine of Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore, 308232 Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
- Institut National de La Recherche Agronomique (INRA), UMR1331 ToxAlim, Toulouse, France
| | - Gerald F. Watts
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine, University of Western Australia, Perth, Australia
| | - Shizuya Yamashita
- Rinku General Medical Center, Izumisano, Osaka Japan
- Department of Community Medicine, Osaka University Graduate School of Medicine, Suita, Osaka Japan
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka Japan
| | - Koutaro Yokote
- Department of Endocrinology, Hematology and Gerontology, Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Alberto Zambon
- Department of Medicine-DIMED, University of Padua, Padua, Italy
| | - Peter Libby
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
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Yamashita S, Masuda D, Matsuzawa Y. Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases. J Atheroscler Thromb 2019; 26:389-402. [PMID: 30930344 PMCID: PMC6514171 DOI: 10.5551/jat.48918] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-cholesterol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates' clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for better efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyceride reduction and HDL-C elevation. Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creatinine or decrease the estimated glomerular filtration rate. There were extremely few drug interactions even when it was used concomitantly with various statins. Furthermore, unlike many of the conventional fibrates that are renal excretory-type drugs, pemafibrate is excreted into the bile, so it can be safely used even in patients with impaired renal function and there is no increase in its blood concentration. This novel SPPARMα, pemafibrate, has superior benefit-risk balance compared to conventional fibrates and can be used for patients for whom it was difficult to use existing fibrates, including those who are taking statins and those with renal dysfunction. A large-scale trial PROMINENT using pemafibrate for patients with type 2 diabetes is in progress. In the current review, the latest data on pemafibrate will be summarized.
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Affiliation(s)
- Shizuya Yamashita
- Department of Cardiology, Rinku General Medical Center.,Department of Community Medicine, Osaka University Graduate School of Medicine.,Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
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31
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Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells. Sci Rep 2019; 9:4703. [PMID: 30886225 PMCID: PMC6423112 DOI: 10.1038/s41598-019-41253-7] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 03/04/2019] [Indexed: 01/04/2023] Open
Abstract
Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.
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32
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Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, De Bosscher K. Molecular Actions of PPARα in Lipid Metabolism and Inflammation. Endocr Rev 2018; 39:760-802. [PMID: 30020428 DOI: 10.1210/er.2018-00064] [Citation(s) in RCA: 531] [Impact Index Per Article: 75.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 07/10/2018] [Indexed: 12/13/2022]
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor of clinical interest as a drug target in various metabolic disorders. PPARα also exhibits marked anti-inflammatory capacities. The first-generation PPARα agonists, the fibrates, have however been hampered by drug-drug interaction issues, statin drop-in, and ill-designed cardiovascular intervention trials. Notwithstanding, understanding the molecular mechanisms by which PPARα works will enable control of its activities as a drug target for metabolic diseases with an underlying inflammatory component. Given its role in reshaping the immune system, the full potential of this nuclear receptor subtype as a versatile drug target with high plasticity becomes increasingly clear, and a novel generation of agonists may pave the way for novel fields of applications.
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Affiliation(s)
- Nadia Bougarne
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Basiel Weyers
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Sofie J Desmet
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
| | - Julie Deckers
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Laboratory of Immunoregulation, VIB Center for Inflammation Research, Ghent (Zwijnaarde), Belgium
| | - David W Ray
- Division of Metabolism and Endocrinology, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester, United Kingdom
| | - Bart Staels
- Université de Lille, U1011-European Genomic Institute for Diabetes, Lille, France
- INSERM, U1011, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Karolien De Bosscher
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Receptor Research Laboratories, Nuclear Receptor Laboratory, VIB Center for Medical Biotechnology, Ghent, Belgium
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Dong T, Lyu J, Imachi H, Kobayashi T, Fukunaga K, Sato S, Ibata T, Yoshimoto T, Yonezaki K, Iwama H, Zhang G, Murao K. Selective peroxisome proliferator-activated receptor-α modulator K-877 regulates the expression of ATP-binding cassette transporter A1 in pancreatic beta cells. Eur J Pharmacol 2018; 838:78-84. [PMID: 30201376 DOI: 10.1016/j.ejphar.2018.09.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/06/2018] [Accepted: 09/06/2018] [Indexed: 10/28/2022]
Abstract
ATP-binding cassette transporter A1 (ABCA1) protein is a pivotal regulator of cholesterol and phospholipid efflux from cells to high-density lipoprotein (HDL) particles. Pancreatic ABCA1 functions in beta cell cholesterol homeostasis and affects insulin secretion. We investigated the effect of pemafibrate (K-877), a novel selective PPARα modulator (SPPARMα), on pancreatic ABCA1 expression. In vivo experiment, mice were divided into four treatment groups, namely, normal food plus placebo, high fat diet (HFD) plus placebo, normal food plus K-877 (0.3 mg/kg/day), or HFD plus K-877 (0.3 mg/kg/day), and treated for eight weeks. The results in vitro experiment indicate that K-877 treatment increased levels of ABCA1 mRNA, as well as protein, subsequently reduced the cellular cholesterol content in INS-1 cells. PPARα specific antagonist GW6471 attenuate K-877 induced ABCA1 expression in INS-1 cells. ABCA1 promoter activity increased with K-877 treatment at concentration 1 μM and 10 μM. Glucose-stimulated insulin secretion was ameliorated by K-877 treatment in INS-1 cells and isolated mouse islets. Although the expression of ABCA1 was reduced in mice with HFD treatment, both ABCA1 protein and mRNA levels were increased in mice with K-877 treatment. K-877 treatment improved glucose intolerance induced by HFD in mice. These findings raise the possibility that K-877 may affect insulin secretion by controlling ABCA1 expression in pancreatic beta cells.
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Affiliation(s)
- Tao Dong
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
| | - Jingya Lyu
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Hitomi Imachi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Toshihiro Kobayashi
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Kensaku Fukunaga
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Seisuke Sato
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Tomohiro Ibata
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Takuo Yoshimoto
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Kazuko Yonezaki
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Guoxing Zhang
- Department of Physiology and Neuroscience, Medical College of Soochow University, 199 Ren-Ai Road, Dushu Lake Campus, Suzhou Industrial Park, Suzhou 215123, China
| | - Koji Murao
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
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Perakakis N, Ghaly W, Peradze N, Boutari C, Batirel S, Douglas VP, Mantzoros CS. Research advances in metabolism 2017. Metabolism 2018; 83:280-289. [PMID: 29378200 DOI: 10.1016/j.metabol.2018.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 01/19/2018] [Indexed: 11/19/2022]
Affiliation(s)
- Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Wael Ghaly
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Physiology, Fayoum University, Fayoum, Egypt
| | - Natia Peradze
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Chrysoula Boutari
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Saime Batirel
- Department of Medical Biochemistry, Faculty of Medicine, Marmara University, Istanbul 34854, Turkey; Genetic and Metabolic Diseases Research Center (GEMHAM), Marmara University, Istanbul 34854, Turkey
| | - Vivian Paraskevi Douglas
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Wu R, Liu X, Yin J, Wu H, Cai X, Wang N, Qian Y, Wang F. IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice. Metabolism 2018; 83:18-24. [PMID: 29336982 DOI: 10.1016/j.metabol.2018.01.002] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 12/24/2017] [Accepted: 01/08/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND OBJECTIVE Interleukin 6 (IL-6) has been identified as a key mediator in inflammation, immune responses and glucose metabolism. In this study, we assessed the effects of an IL-6 receptor antibody on diabetic nephropathy in a mouse model of type 2 diabetes mellitus. METHODS Twelve week old male db/db mice were treated with Tocilizumab (an IL-6 receptor antibody), normal IgG1 control antibody, insulin or normal saline for 12 weeks. Renal injury, inflammation and insulin resistance were assessed. RESULTS Db/db mice treated with Tocilizumab exhibited reduced proteinuria and glomerular mesangial matrix accumulation compared to db/db + IgG controls. Additionally, Tocilizumab suppressed inflammatory response, oxidative stress and the IL-6 signaling pathway in the diabetic kidneys. It is noteworthy that blockade of IL-6 receptor blunted the activation of NLRP3 inflammasome partly through inhibition of IL-17A. Furthermore, insulin resistance assessed by glucose tolerance test, was ameliorated by Tocilizumab treatment. CONCLUSIONS The protective effects of an IL-6 receptor blockade against diabetic renal injury may be due to decreased insulin resistance and inhibition of the inflammasome.
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Affiliation(s)
- Rui Wu
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Xuanchen Liu
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Jiangsu University Affiliated Shanghai Eighth People's Hospital, Shanghai 200233, China
| | - Jianyong Yin
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Huijuan Wu
- Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiulei Cai
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
| | - Niansong Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Youcun Qian
- Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China
| | - Feng Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Jiangsu University Affiliated Shanghai Eighth People's Hospital, Shanghai 200233, China.
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Zheng S, Ren X, Han T, Chen Y, Qiu H, Liu W, Hu Y. Fenofibrate attenuates fatty acid-induced islet β-cell dysfunction and apoptosis via inhibiting the NF-κB/MIF dependent inflammatory pathway. Metabolism 2017; 77:23-38. [PMID: 28941594 DOI: 10.1016/j.metabol.2017.09.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Revised: 09/04/2017] [Accepted: 09/05/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND Fatty acid-induced lipotoxicity and macrophage migration inhibitory factor (MIF) affect pancreatic β-cell function, and may promote the development of diabetes mellitus. However, the association of lipotoxicity with MIF and the effect of Fenofibrate on β-cell function remain unknown. METHODS LPL+/- mice and MIN6 cells stimulated with palmitic acid (PA) were utilized as models of lipid metabolism disorders. Factors associated with insulin secretion and apoptosis were assessed in the presence or absence of Fenofibrate. The possible mechanisms of lipotoxicity-induced β-cell dysfunction were also explored. RESULTS Fenofibrate effectively improved lipid accumulation in pancreatic β-cells, increased glucose-stimulated insulin secretion and β-cell mass, and significantly downregulated pro-apoptotic molecules, at the gene and protein levels, both in vivo and in vitro. Additionally, elevated MIF levels in serum from LPL+/- mice and PA-treated MIN6 cells were starkly decreased after Fenofibrate administration. Mechanistic analysis indicated that NF-κB signaling was remarkably triggered, which could further activate MIF transcription. Furthermore, Fenofibrate exerted beneficial effects on fatty acid-induced β-cell dysfunction likely by inhibiting the NF-κB/MIF dependent inflammatory response. CONCLUSIONS Fenofibrate ameliorates lipotoxicity-induced β-cell dysfunction and apoptosis by inhibiting the NF-κB/MIF inflammatory pathway. These findings provide novel insights into the treatment of lipotoxicity-induced metabolic disorders.
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Affiliation(s)
- Shuang Zheng
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xingxing Ren
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tingting Han
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yawen Chen
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Huiying Qiu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wei Liu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Yaomin Hu
- Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol 2017; 16:124. [PMID: 28978316 PMCID: PMC5628452 DOI: 10.1186/s12933-017-0602-y] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor-cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII. Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation. A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.
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Han Q, Zhu H, Chen X, Liu Z. Non-genetic mechanisms of diabetic nephropathy. Front Med 2017; 11:319-332. [PMID: 28871454 DOI: 10.1007/s11684-017-0569-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/22/2017] [Indexed: 12/12/2022]
Abstract
Diabetic nephropathy (DN) is one of the most common microvascular complications in diabetes mellitus patients and is characterized by thickened glomerular basement membrane, increased extracellular matrix formation, and podocyte loss. These phenomena lead to proteinuria and altered glomerular filtration rate, that is, the rate initially increases but progressively decreases. DN has become the leading cause of end-stage renal disease. Its prevalence shows a rapid growth trend and causes heavy social and economic burden in many countries. However, this disease is multifactorial, and its mechanism is poorly understood due to the complex pathogenesis of DN. In this review, we highlight the new molecular insights about the pathogenesis of DN from the aspects of immune inflammation response, epithelial-mesenchymal transition, apoptosis and mitochondrial damage, epigenetics, and podocyte-endothelial communication. This work offers groundwork for understanding the initiation and progression of DN, as well as provides ideas for developing new prevention and treatment measures.
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Affiliation(s)
- Qiuxia Han
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, China
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Hanyu Zhu
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, China.
| | - Xiangmei Chen
- Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Diseases, Beijing, 100853, China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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