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Dahiya K, Prashant P, Dhankhar R, Dhankhar K, Kumar S, Vashist S. Lipocalin-2 as a biomarker for diabetic nephropathy. World J Meta-Anal 2023; 11:92-101. [DOI: 10.13105/wjma.v11.i4.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/11/2023] [Accepted: 03/29/2023] [Indexed: 04/14/2023] Open
Abstract
Diabetes is a major global public health issue. The prevalence of type 1 diabetes is comparatively static, as hereditary and genetic causes are involved, while type 2 diabetes (T2D) prevalence is increasing day by day. T2D is associated with chronic complications, including diabetic neuropathy (DN), nephropathy, retinopathy, and other complications like diabetic foot. DN is the main complication of both types of diabetes. DN can be diagnosed by routine laboratory tests, microalbuminuria > 300 mg/24 h, and a gradual decrease in glomerular filtration rate. As the appearance of microalbuminuria is a late manifestation, an early marker for renal damage is needed. Lipocalin-2, also known as neutrophil gelatinase-associated lipocalin (NGAL), is a small protein purified from neutrophil granules and a good marker for kidney disease. NGAL is a transporter protein responsible for many physiological processes, such as inflammation, generation of the immune response, and metabolic homeostasis. NGAL has been reported to depict the early changes in renal damage when urine microalbumin is still undetecable. Therefore, elucidating the role of NGAL in detecting DN and understanding its mechanism can help establish it as a potential early marker for DN.
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Affiliation(s)
- Kiran Dahiya
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Praveen Prashant
- Department of Biochemistry, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, Haryana, India
| | - Rakesh Dhankhar
- Department of Radiation Oncology, Pt BD Sharma Post Graduate Institute of Medical Sciences, Rohtak 124001, India
| | - Kumud Dhankhar
- Phase III, JSS Medical College, Mysuru 570015, Karnataka, India
| | | | - Sonia Vashist
- Department of Dermatology, Dr Sonia’s Dermatology Clinic, Rewari 123401, Haryana, India
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2-Methoxyestradiol TPGS Micelles Attenuate Cyclosporine A-Induced Nephrotoxicity in Rats through Inhibition of TGF-β1 and p-ERK1/2 Axis. Antioxidants (Basel) 2022; 11:antiox11081499. [PMID: 36009218 PMCID: PMC9405159 DOI: 10.3390/antiox11081499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 01/25/2023] Open
Abstract
The immunosuppressant cyclosporine A (CSA) has been linked to serious renal toxic effects. Although 2-methoxyestradiol (2ME) possesses a wide range of pharmacological abilities, it suffers poor bioavailability after oral administration. The purpose of this study was to evaluate the potential of 2ME loaded D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles to prevent CSA-induced nephrotoxicity in rats. A 2ME-TPGS was prepared and showed particle size of 44.3 ± 3.5 nm with good entrapment efficiency and spherical structures. Male Wistar rats were divided into 5 groups, namely: Control, Vehicle, CSA, CSA + 2ME-Raw, and CSA + 2ME-Nano. CSA was injected daily at a SC dose of 20 mg/kg. Both 2ME-Raw and 2ME-Nano were given daily at oral doses of 5 mg/kg. Treatments continued for three successive weeks. 2ME-TPGS exerted significant protective effects against CSA nephrotoxicity. This was evidenced in ameliorating deterioration of renal functions, attenuation of pathological changes in kidney tissues, exerting significant anti-fibrotic, antioxidant, and anti-inflammatory effects together with significant anti-apoptotic effects. Western blot analyses showed both 2ME-Raw and 2ME-Nano significantly inhibited protein expression of TGF-β1 and phospho-ERK (p-ERK). It was observed that 2ME-TPGS, in almost all experiments, exerted superior protective effects as compared with 2ME-Raw. In conclusion, 2ME loaded in a TPGS nanocarrier possesses significant protective activities against CSA-induced kidney injury in rats. This is attributable to 2ME anti-fibrotic, antioxidant, anti-inflammatory, and anti-apoptotic activities which are mediated at least partly by inhibition of TGF-β1/p-ERK axis.
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Nie J, Hao W, Dou X, Wang X, Luo N, Lan HY, Yu X. Effects of SMAD7 Overexpression on Peritoneal Inflammation in a Rat Peritoneal Dialysis Model. Perit Dial Int 2020. [DOI: 10.1177/089686080702700520] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Objective Transforming growth factor-beta (TGF-β) has been shown to play a role in peritoneal complications due to long-term peritoneal dialysis (PD). In this study, we examined the effects of the TGF-β signaling pathway on peritoneal inflammation associated with PD in rats by over-expressing Smad7, an inhibitor of TGF-β/Smad signaling. Methods Peritoneal inflammation was induced in male Sprague-Dawley rats by intraperitoneal injections of 4.25% glucose dialysate (100 mg/kg body weight) daily for 4 weeks, with the addition of lipopolysaccharides (0.6 mg/kg body weight) on days 8, 10, 12, 22, 24, and 26. Peritoneal Smad7 gene transfer was achieved using an ultrasound microbubble mediated, doxycycline regulated, Smad7-expressing plasmid on day 0 and day 14 after initiation of PD. An empty vector was used as control. All rats were sacrificed after 4 weeks of PD. Peritoneal inflammatory response, including infiltration of total leukocytes (OX-1 positive) and macrophages (ED-1 positive) and expression of interleukin (IL)-1β) and tumor necrosis factor-alpha (TNF-α), was examined by immunofluorescence and RT-PCR. Results After PD, peritoneal inflammation developed in control animals, as demonstrated by an increase in the number of OX-1-positive and ED-1-positive cells and upregulation of IL-1β and TNF-α mRNA and protein expression. In contrast, in animals treated with Smad7 gene transfer, IL-1β and TNF-α expression and OX-1-positive and ED-1-positive cell infiltration were significantly inhibited. Furthermore, prevention of peritoneal inflammation by overexpression of Smad7 was associated with inhibition of phosphorylation of Smad2/3, a downstream of the TGF-β signaling pathway, as well as TGF-β1 expression. Conclusion Overexpression of Smad7 suppresses peritoneal inflammation induced by high glucose and lipopolysaccharides. The ability of Smad7 gene transfer to inhibit peritoneal inflammation indicates that targeting TGF-β/Smad signaling may represent a new therapeutic strategy for the treatment of peritoneal complications associated with PD.
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Affiliation(s)
- Jing Nie
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Wenke Hao
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Xianrui Dou
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Xin Wang
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Ning Luo
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
| | - Hui Y. Lan
- Department of Medicine, Center for Inflammatory Diseases and Molecular Therapies, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Xueqing Yu
- Department of Nephrology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou
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Zhang J, Liu J, Qin X. Advances in early biomarkers of diabetic nephropathy. ACTA ACUST UNITED AC 2018; 64:85-92. [PMID: 29561946 DOI: 10.1590/1806-9282.64.01.85] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 09/09/2017] [Indexed: 01/06/2023]
Abstract
Diabetic nephropathy is the main cause of chronic kidney disease, and represents the most common and serious complication of diabetes. The exact pathogenesis is complex and not elucidated. Several factors and mechanisms contribute to the development and outcome of diabetic nephropathy. An early diagnosis and intervention may slow down disease progression. A variety of biological markers associated with diabetic nephropathy were found in recent years, which was important for predicting the occurrence and development of the disease. Therefore, this article provides an overview of early biomarkers that are associated with diabetic nephropathy.
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Affiliation(s)
- Jin Zhang
- Masters Student, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianhua Liu
- MD, PhD. Associate Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaosong Qin
- MD, PhD. Professor of Laboratory Medicine, Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
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Herrera GA, Teng J, Zeng C, Xu H, Liang M, Alexander JS, Liu B, Boyer C, Turbat-Herrera EA. Phenotypic plasticity of mesenchymal stem cells is crucial for mesangial repair in a model of immunoglobulin light chain-associated mesangial damage. Ultrastruct Pathol 2018; 42:262-288. [PMID: 29668344 DOI: 10.1080/01913123.2018.1449772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Mesangiopathies produced by glomerulopathic monoclonal immunoglobulin light chains (GLCs) acting on the glomerular mesangium produce two characteristic lesions: AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD). In both cases, the pathology is centered in the mesangium, where initial and progressive damage occurs. In AL-Am the mesangial matrix is destroyed and replaced by amyloid fibrils and in LCDD, the mesangial matrix is increased and remodeled. The collagen IV rich matrix is replaced by tenascin. In both conditions, mesangial cells (MCs) become apoptotic as a direct effect of the GLCs. MCs were incubated in-vitro with GLCs and animal kidneys were perfused ex-vivo via the renal artery with GLCs, producing expected lesions, and then mesenchymal stem cells (MSCs) were added to both platforms. Each of the two platforms provided unique information that when put together created a comprehensive evaluation of the processes involved. A "cocktail" with growth and differentiating factors was used to study its effect on mesangial repair. MSCs displayed remarkable phenotypic plasticity during the repair process. The first role of the MSCs after migrating to the affected areas was to dispose of the amyloid fibrils (in AL-Am), the altered mesangial matrix (in LCDD) and apoptotic MCs/debris. To accomplish this task, MSCs transformed into facultative macrophages acquiring an abundance of lysosomes and endocytotic capabilities required to engage in phagocytic functions. Once the mesangial cleaning was completed, MSCs transformed into functional MCs restoring the mesangium to normal. "Cocktail" made the repair process more efficient.
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Affiliation(s)
- Guillermo A Herrera
- a Departments of Pathology and Translational Pathobiology and Cell Biology and Anatomy , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Jiamin Teng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chun Zeng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Hongzhi Xu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Man Liang
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - J Steven Alexander
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Bing Liu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chris Boyer
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Elba A Turbat-Herrera
- d Departments of Pathology and Translational Pathobiology , Medicine, and Cell Biology and Anatomy, Louisiana State Health Sciences Center , Shreveport , LA , USA
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Ravinal RC, Costa RS, Coimbra TM, Dantas M, dos Reis MA. Mast cells, TGF-β1 and myofibroblasts expression in lupus nephritis outcome. Lupus 2016; 14:814-21. [PMID: 16302676 DOI: 10.1191/0961203305lu2188oa] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Renal biopsies of 69 patients with lupus nephritis were studied according to the WHO classification. The aim of the present study was to correlate the interstitial tryptase-positive mast cells with the interstitial TGF-β1 and α-SM actin expression and clinical outcome of lupus nephritis, and identify the pathological role of the interstitial tryptase-positive mast cells in lupus nephritis. The mean follow-up time was 70.7 ± 54.4 months. Eight patients were grouped as WHO class II lupus nephritis, 15 patients as class III, 28 patients as class IV and 18 patients as class V. Interstitial tryptase-positive mast cells were not correlated with clinical outcome and interstitial TGF-β1 expression in lupus nephritis. Interstitial tryptase-positive mast cells were correlated with tubulo-interstitial α-SM actin expression for WHO class V lupus nephritis, but not to the other classes. In conclusion, in spite of interstitial tryptase-positive mast cells being related to renal interstitial fibrosis process, their expression according to the clinical outcome of lupus nephritis was not significant.
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Affiliation(s)
- R Cuan Ravinal
- Department of Pathology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
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Li Y, Shen Y, Li M, Su D, Xu W, Liang X, Li R. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes. Mol Cell Biochem 2015; 405:233-41. [PMID: 25920446 DOI: 10.1007/s11010-015-2414-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 04/18/2015] [Indexed: 12/14/2022]
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.
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Affiliation(s)
- Yanjiao Li
- Department of Nephrology, Shanxi Provincial People's Hospital, The Affiliated People's Hospital of Shanxi Medical University, Taiyuan, 030012, Shanxi, China
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Li L, Shen Y, Ding Y, Liu Y, Su D, Liang X. Hrd1 participates in the regulation of collagen I synthesis in renal fibrosis. Mol Cell Biochem 2013; 386:35-44. [DOI: 10.1007/s11010-013-1843-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 09/26/2013] [Indexed: 10/26/2022]
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Wei X, Xia Y, Li F, Tang Y, Nie J, Liu Y, Zhou Z, Zhang H, Hou FF. Kindlin-2 mediates activation of TGF-β/Smad signaling and renal fibrosis. J Am Soc Nephrol 2013; 24:1387-1398. [PMID: 23723426 PMCID: PMC3752947 DOI: 10.1681/asn.2012101041] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2012] [Accepted: 03/28/2013] [Indexed: 01/05/2023] Open
Abstract
Activation of TGF-β/Smad signaling plays a central role in the pathogenesis of tubulointerstitial fibrosis, but the mechanisms underlying the initial interaction of the TGF-β receptor with Smads, leading to their activation, remain unclear. Here, we found that Kindlin-2, an integrin-binding protein, physically mediated the interaction of the TGF-β type I receptor (TβRI) with Smad3 in human kidney tubular epithelial cells. Kindlin-2 bound to TβRI through its FERM domain and to Smad3 through its N terminus. Overexpression of Kindlin-2 increased TGF-β-induced Smad3 activation. Knockdown of Kindlin-2 significantly suppressed the engagement of TβRI with Smad3 and inhibited TGF-β-induced Smad3 activation, as well as the expression of its target genes. Neither transfection of a Kindlin-2 mutant incapable of binding to β1 integrin nor knockdown of β1 integrin influenced the effect of Kindlin-2 on TGF-β1-induced Smad3 activation, indicating that this effect is independent of integrin. Kindlin-2 expression was markedly increased, predominantly in renal tubular epithelial cells, both in the unilateral ureteral obstruction model of kidney fibrosis and in human tissue exhibiting tubulointerstitial fibrosis. Furthermore, in the unilateral ureteral obstruction model, knocking down Kindlin-2 significantly inhibited activation of TGF-β/Smad signaling, decreased the expression of matrix genes, and ameliorated fibrosis. In summary, Kindlin-2 physically interacts with both TβRI and Smad3, promoting the activation of TGF-β/Smad signaling and contributing to the pathogenesis of tubulointerstitial fibrosis. Blockade of Kindlin-2 might be a rational therapeutic strategy for the treatment of fibrotic kidney diseases.
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Affiliation(s)
- Xiaofan Wei
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and
| | - Yang Xia
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of China, and Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, China
| | - Feng Li
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of China, and Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, China
| | - Yan Tang
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of China, and Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, China
| | - Jing Nie
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and
| | - Youhua Liu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and
| | - Zhanmei Zhou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and
| | - Hongquan Zhang
- Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education of China, and Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, China
| | - Fan Fan Hou
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Institute of Nephrology Guangdong Province, Key Laboratory for Organ Failure Research, Ministry of Education, Guangzhou, China; and
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Mori Y, Hirano T. Ezetimibe alone or in combination with pitavastatin prevents kidney dysfunction in 5/6 nephrectomized rats fed high-cholesterol. Metabolism 2012; 61:379-88. [PMID: 21868047 DOI: 10.1016/j.metabol.2011.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 07/07/2011] [Accepted: 07/08/2011] [Indexed: 01/13/2023]
Abstract
We attempted to elucidate the relationship between cholesterol absorption and kidney damage by investigating the renoprotective effect of ezetimibe, a cholesterol absorption inhibitor, in 5/6 nephrectomized rats (Nx). The Nx or sham-operated rats (Sham) were fed 1% high-cholesterol diet (HC) containing ezetimibe (10 mg/[kg d]), pitavastatin (3 mg/[kg d]), or both for 8 weeks. Pathological changes, endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA), and oxidative stress were assessed in the kidney. The Sham fed HC exhibited hypercholesterolemia and glomerulosclerosis with macrophage infiltration in the kidney, and ezetimibe attenuated these changes. The Nx exhibited hypercholesterolemia, increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), glomerulosclerosis with macrophage infiltration and interstitial fibrosis, and downregulation of eNOS mRNA. The HC increased cholesterol further and worsened the kidney damage with increased 8-OHdG. Ezetimibe attenuated the hypercholesterolemia, kidney dysfunction, and pathological changes. The beneficial effects of ezetimibe were significantly associated with reduced 8-OHdG (P < .01). Pitavastatin did not reduce cholesterol or 8-OHdG, but it did significantly suppress the kidney damage with upregulated eNOS mRNA by 2.5-fold (P < .02). The combination of ezetimibe and pitavastatin synergistically ameliorated the kidney damage. The kidney dysfunction and pathological changes were significantly associated with cholesterol, markers of cholesterol absorption (campesterol and cholestanol), and 8-OHdG (P < .001-.05). Multiple regression analysis revealed that the markers of cholesterol absorption were independently associated with the kidney damage. Ezetimibe confers renoprotective effects by inhibiting cholesterol absorption, which in turn reduces oxidative stress; and pitavastatin additively ameliorates kidney damage by increasing NO production via mechanisms independent of cholesterol reduction.
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Affiliation(s)
- Yusaku Mori
- Department of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
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Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 2011; 347:141-54. [PMID: 22105921 DOI: 10.1007/s00441-011-1275-6] [Citation(s) in RCA: 222] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Accepted: 10/25/2011] [Indexed: 02/07/2023]
Abstract
Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.
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Liu N, Tolbert E, Pang M, Ponnusamy M, Yan H, Zhuang S. Suramin inhibits renal fibrosis in chronic kidney disease. J Am Soc Nephrol 2011; 22:1064-75. [PMID: 21617121 DOI: 10.1681/asn.2010090956] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The activation of cytokine and growth factor receptors associates with the development and progression of renal fibrosis. Suramin is a compound that inhibits the interaction of several cytokines and growth factors with their receptors, but whether suramin inhibits the progression of renal fibrosis is unknown. Here, treatment of cultured renal interstitial fibroblasts with suramin inhibited their activation induced by TGF-β1 and serum. In a mouse model of obstructive nephropathy, administration of a single dose of suramin immediately after ureteral obstruction abolished the expression of fibronectin, largely suppressed expression of α-SMA and type I collagen, and reduced the deposition of extracellular matrix proteins. Suramin also decreased the expression of multiple cytokines including TGF-β1 and reduced the interstitial infiltration of leukocytes. Moreover, suramin decreased expression of the type II TGF-β receptor, blocked phosphorylation of the EGF and PDGF receptors, and inactivated several signaling pathways associated with the progression of renal fibrosis. In a rat model of CKD, suramin abrogated proteinuria, limited the decline of renal function, and prevented glomerular and tubulointerstitial damage. Collectively, these findings indicate that suramin is a potent antifibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
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Affiliation(s)
- Na Liu
- Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island, USA
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Taguchi T, Nazneen A, Al-Shihri AA, A. Turkistani K, Razzaque MS. Heat shock protein 47: a novel biomarker of phenotypically altered collagen-producing cells. Acta Histochem Cytochem 2011; 44:35-41. [PMID: 21614164 PMCID: PMC3096080 DOI: 10.1267/ahc.11001] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 02/18/2011] [Indexed: 01/15/2023] Open
Abstract
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen-producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen-producing cells.
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Affiliation(s)
- Takashi Taguchi
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
| | - Arifa Nazneen
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
| | - Abdulmonem A. Al-Shihri
- Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine
| | | | - Mohammed S. Razzaque
- Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine
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Pozdzik AA, Berton A, Schmeiser HH, Missoum W, Decaestecker C, Salmon IJ, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy revisited: a place for innate and adaptive immunity? Histopathology 2011; 56:449-63. [PMID: 20459552 DOI: 10.1111/j.1365-2559.2010.03509.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS The histological features of aristolochic acid nephropathy (AAN) consist of paucicellular interstitial fibrosis, severe tubular atrophy, and almost intact glomeruli with media lesions of interlobular arteries. As an early phase of interstitial inflammation preceded peritubular fibrosis in the rat model of AAN, the aim was to investigate the presence of inflammatory cells in human AAN. METHODS AND RESULTS Reports of confirmed cases and case series of AAN were reviewed in terms of interstitial inflammation and found to have very conflicting results. This prompted us to search for and characterize inflammatory cells within the native kidneys provided from four end-stage AAN patients. Prior aristolochic acid exposure was attested by the intrarenal presence of the typical aristolactam I-derived DNA adduct. Besides the tubulointerstitial lesions usually seen in the cortex, a massive infiltration of macrophages, T and B lymphocytes was detected by immunohistochemistry in the medullary rays and in the outer medullae with some extension to the upper cortical labyrinth. CONCLUSIONS In parallel with histological findings reported in the rat model, inflammatory cells are present preferentially in the interstitium of the medullary rays and of the outer medulllae in renal interstitium from human AAN cases, even in the terminal stages. Further studies must be undertaken to determine the respective roles of innate and adaptive immunity in the progression of AAN.
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Affiliation(s)
- Agnieszka A Pozdzik
- Unit of Experimental Nephrology, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
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Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications. J Transl Med 2011; 9:13. [PMID: 21251296 PMCID: PMC3034700 DOI: 10.1186/1479-5876-9-13] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Accepted: 01/20/2011] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed.
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García-Sánchez O, López-Hernández FJ, López-Novoa JM. An integrative view on the role of TGF-beta in the progressive tubular deletion associated with chronic kidney disease. Kidney Int 2010; 77:950-5. [PMID: 20336053 DOI: 10.1038/ki.2010.88] [Citation(s) in RCA: 119] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Transforming growth factor-beta (TGF-beta) is a cytokine known to participate in several processes related to the development of chronic kidney disease (CKD), including tubular degeneration. This is thought to occur mainly through apoptosis and epithelial-to-mesenchymal transition (EMT) of tubule epithelial cells, which give rise to a reduction of the tubular compartment and a scarring-like, fibrotic healing process of the interstitial compartment. In vivo blockade of TGF-beta action has been shown to reduce CKD-associated tubular damage. However, a direct action of TGF-beta on tubule cells is controversial as the underlying mechanism. On the one hand, TGF-beta is known to induce EMT of tubular cells, although its incidence in vivo can hardly explain the extent of the damage. On the other hand, a few publications have reported that TGF-beta induces a mild degree of apoptosis in cultured tubular cells. This most likely reflects the consequence of the cell-cycle arrest rather than a direct pro-apoptotic effect of TGF-beta. The implications of these observations are analyzed in the pathological context, where normal tubular cells do not normally proliferate, but they might divide for repair purposes. Furthermore, renal fibrosis, a TGF-beta-mediated event, is integrated as a potential, indirect effect contributing to tubule deletion.
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Affiliation(s)
- Omar García-Sánchez
- Unidad de Fisiopatología Renal y Cardiovascular, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
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Chiang TA, Yang YL, Yang YY, Hu MH, Wu PF, Liu SF, Huang RM, Liao TN, Hung CY, Hung TJ, Lee TC. Hyperosmolarity enhanced susceptibility to renal tubular fibrosis by modulating catabolism of type I transforming growth factor-beta receptors. J Cell Biochem 2010; 109:663-671. [PMID: 20091742 DOI: 10.1002/jcb.22444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hyperosmolarity plays an essential role in the pathogenesis of diabetic tubular fibrosis. However, the mechanism of the involvement of hyperosmolarity remains unclear. In this study, mannitol was used to evaluate the effects of hyperosmolarity on a renal distal tubule cell line (MDCK). We investigated transforming growth factor-beta receptors and their downstream fibrogenic signal proteins. We show that hyperosmolarity significantly enhances the susceptibility to exogenous transforming growth factor (TGF)-beta1, as mannitol (27.5 mM) significantly enhanced the TGF-beta1-induced increase in fibronectin levels compared with control experiments (5.5 mM). Specifically, hyperosmolarity induced tyrosine phosphorylation on TGF-beta RII at 336 residues in a time (0-24 h) and dose (5.5-38.5 mM) dependent manner. In addition, hyperosmolarity increased the level of TGF-beta RI in a dose- and time-course dependent manner. These observations may be closely related to decreased catabolism of TGF-beta RI. Hyperosmolarity significantly downregulated the expression of an inhibitory Smad (Smad7), decreased the level of Smurf 1, and reduced ubiquitination of TGF-beta RI. In addition, through the use of cycloheximide and the proteasome inhibitor MG132, we showed that hyperosmolarity significantly increased the half-life and inhibited the protein level of TGF-beta RI by polyubiquitination and proteasomal degradation. Taken together, our data suggest that hyperosmolarity enhances cellular susceptibility to renal tubular fibrosis by activating the Smad7 pathway and increasing the stability of type I TGF-beta receptors by retarding proteasomal degradation of TGF-beta RI. This study clarifies the mechanism underlying hyperosmotic-induced renal fibrosis in renal distal tubule cells.
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Affiliation(s)
- Tai-An Chiang
- Department of Medical Technology, Graduate Institute of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan.
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JNK1/2 siRNA inhibits transforming-growth factor-beta1-induced connective tissue growth factor expression and fibrotic function in THSFs. Mol Cell Biochem 2009; 335:83-9. [PMID: 19763793 DOI: 10.1007/s11010-009-0245-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Accepted: 09/02/2009] [Indexed: 02/06/2023]
Abstract
Transforming-growth factor-beta1 (TGF-beta1) plays an important role in fibrosis by inducing connective tissue growth factor (CTGF) expression. In cornea, however, signaling pathway in the process is unclear. In this paper, real-time RT-PCR and Western blot analysis were used to examine the expression and TGF-beta1-induced upregulation of CTGF in telomerase-immortalized human cornea stroma fibroblast cells (THSFs). A detailed molecular mechanism for TGF-beta1-mediated cell proliferation and collagen I production was then investigated by detecting the activation of JNK pathway in TGF-beta1-stimulated THSFs and blocking the JNK pathway using JNK1/2 siRNA. Both TGF-beta1 and CTGF clearly induced cell proliferation in THSFs which was inhibited by functional blocking CTGF by anti-CTGF antibody. Blocking JNK pathway by JNK1/2 siRNA significantly inhibited induction of CTGF by TGF-beta1. Taken together, the data indicate that CTGF is critical to the fibrosis process in wounded human cornea, acting via upregulation and activation of JNK signaling pathway.
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Daniel C, Wagner A, Hohenstein B, Hugo C. Thrombospondin-2 therapy ameliorates experimental glomerulonephritis via inhibition of cell proliferation, inflammation, and TGF-beta activation. Am J Physiol Renal Physiol 2009; 297:F1299-309. [PMID: 19726547 DOI: 10.1152/ajprenal.00254.2009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
We recently identified thrombospondin-2 (TSP-2) as an endogenous regulator of matrix remodelling and inflammation in experimental kidney disease by studying TSP-2-deficient mice. In this study, we asked whether systemic TSP-2 overexpression via thigh muscle transfection is able to ameliorate the time course of the anti-Thy1 glomerulonephritis model. After induction of anti-Thy1 nephritis, rats were transfected either with an overexpression plasmid for TSP-2 or lacZ as a control. Biopsies, urine, and blood samples were taken on days 1, 3, and 6 after disease induction. Muscular overexpression of TSP-2 reduced glomerular transforming growth factor (TGF)-beta activation and glomerular extracellular matrix formation as determined by collagen IV and fibronectin. In addition, activation of mesangial cells to the myofibroblast-like phenotype was also significantly decreased in TSP-2-overexpressing animals. TSP-2 overexpression inhibited both glomerular endothelial and mesangial cell proliferation, resulting in a reduced glomerular cell number and glomerular tuft area. The inflammatory response, as monitored by T cells and antigen-presenting cells, was reduced significantly by TSP-2 overexpression, but influx of macrophages was unchanged. These data demonstrate TSP-2 as a potential therapeutic agent to inhibit the glomerular proliferative and inflammatory response as well as TGF-beta activation and extracellular matrix accumulation in experimental mesangial proliferative glomerulonephritis.
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Affiliation(s)
- Christoph Daniel
- Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
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20
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Pozdzik AA, Salmon IJ, Husson CP, Decaestecker C, Rogier E, Bourgeade MF, Deschodt-Lanckman MM, Vanherweghem JL, Nortier JL. Patterns of interstitial inflammation during the evolution of renal injury in experimental aristolochic acid nephropathy. Nephrol Dial Transplant 2008; 23:2480-91. [PMID: 18385385 DOI: 10.1093/ndt/gfn140] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis. METHODS Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway. RESULTS In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments. CONCLUSION An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway.
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Affiliation(s)
- Agnieszka A Pozdzik
- Department of Nephrology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070 Brussels, Belgium
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Long-term nebivolol administration reduces renal fibrosis and prevents endothelial dysfunction in rats with hypertension induced by renal mass reduction. J Hypertens 2008; 25:2486-96. [PMID: 17984671 DOI: 10.1097/hjh.0b013e3282efeecb] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES D/L-Nebivolol is a lypophilic beta1-adrenergic antagonist which is devoid of intrinsic sympathomimetic activity and can increase nitric oxide (NO) bioavailability with its subsequent vasodilating properties. The purpose of the present work was to assess the effect of long-term nebivolol administration on both renal damage and endothelial dysfunction induced by renal mass reduction (RMR) in rats. Atenolol, which does not increase NO bioavailability, was included in the study as a comparative beta-adrenoceptor antagonist. METHODS Rats were subjected to both right nephrectomy and surgical removal of two-thirds of the left kidney in order to retain approximately one-sixth of the total renal mass. One week after ablation, rats were distributed randomly according to the following experimental groups: control group containing RMR rats without treatment; RMR rats treated daily with nebivolol for 6 months (drinking water, 8 mg/kg per day); and RMR rats treated daily with atenolol for 6 months (drinking water, 80 mg/kg per day). A group of sham-operated animals was also included. RESULTS Administration of either nebivolol or atenolol similarly reduced arterial pressure in comparison with RMR untreated animals; however, animals receiving nebivolol presented lower levels of collagen type I expression as well as lower glomerular and interstitial fibrosis than those receiving atenolol. Urinary excretion of oxidative stress markers were also lower in animals receiving nebivolol than in rats treated with atenolol. Furthermore, nebivolol prevented RMR-induced endothelial dysfunction more efficiently than atenolol. CONCLUSIONS Nebivolol protects against renal fibrosis, oxidative stress and endothelial dysfunction better than equivalent doses, in terms of arterial pressure reduction, of atenolol in a hypertensive model of renal damage induced by RMR.
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Yuan J, Jia R, Bao Y. Beneficial effects of spironolactone on glomerular injury in streptozotocin-induced diabetic rats. J Renin Angiotensin Aldosterone Syst 2008; 8:118-26. [PMID: 17907099 DOI: 10.3317/jraas.2007.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION To investigate the beneficial effects of spironolactone (SPL) on glomerular injury in streptozotocin (STZ)-induced diabetic rats and the possible mechanism. METHODS AND RESULTS STZ-induced diabetic rats were divided into control group, STZ group, and SPL group. Glomerular morphology was observed by light microscopy after the rats were sacrificed after 30 days treatment. The mRNA expressions of transforming growth factor-beta 1 (TGF-beta1) and type-1 plasminogen activator inhibitor (PAI-1) in renal cortex were measured by transcription-polymerase chain reaction (RT-PCR). The protein expressions of PAI-1, fibronectin (FN) and TGF-beta1 were detected by western blotting and immunohistochemistry respectively. In addition, levels of malondialdehyde (MDA) and the activity of antioxidants including superoxide diamutase (SOD), glutathione peroxidase (GSH-PX) in the cortex of kidney were measured. RESULTS In untreated diabetic rats, the glomerular volume, the expression of FN and the urinary albumin excretion increased. The mRNA and protein expression of PAI-1 and TGF-beta1 significantly increased in the STZ group. Treatment with SPL partially reversed these changes. Meanwhile, elevated MDA levels as well as decreased SOD and GSH-PX activities in the cortex of kidney were significantly ameliorated in the treated group. CONCLUSION SPL ameliorates the glomerular injury in STZ-induced early diabetic renal injury, which is closely related with the reduction of PAI-1 and TGF-beta1 expression and the attenuation of oxidative stress.
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Affiliation(s)
- Jun Yuan
- Department of Nephrology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan 430060, Hubei Province, China
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Pozdzik AA, Salmon IJ, Debelle FD, Decaestecker C, Van den Branden C, Verbeelen D, Deschodt-Lanckman MM, Vanherweghem JL, Nortier JL. Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int 2007; 73:595-607. [PMID: 18094681 DOI: 10.1038/sj.ki.5002714] [Citation(s) in RCA: 146] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.
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Affiliation(s)
- A A Pozdzik
- Experimental Nephrology Unit, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
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Lin J, Patel SR, Wang M, Dressler GR. The cysteine-rich domain protein KCP is a suppressor of transforming growth factor beta/activin signaling in renal epithelia. Mol Cell Biol 2006; 26:4577-85. [PMID: 16738323 PMCID: PMC1489124 DOI: 10.1128/mcb.02127-05] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The transforming growth factor beta (TGF-beta) superfamily, including the bone morphogenetic protein (BMP) and TGF-beta/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-beta but inhibited by BMP7. In this report, the effects of KCP on TGF-beta/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A- and TGF-beta1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-beta1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-beta and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-beta activation indicates a critical role for KCP in modulating the responses between these anti- and profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.
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Affiliation(s)
- Jingmei Lin
- Department of Pathology, University of Michigan, MSRB1 4510D, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0650, USA
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Kanamaru Y, Scandiuzzi L, Essig M, Brochetta C, Guérin-Marchand C, Tomino Y, Monteiro RC, Peuchmaur M, Blank U. Mast cell-mediated remodeling and fibrinolytic activity protect against fatal glomerulonephritis. THE JOURNAL OF IMMUNOLOGY 2006; 176:5607-15. [PMID: 16622030 DOI: 10.4049/jimmunol.176.9.5607] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Mast cells are detrimental in several inflammatory diseases; however, their physiological roles are also increasingly recognized. Recent data suggest that mast cells may also be involved in renal diseases. We therefore used congenitally mast cell-deficient W/W(v) mice and normal +/+ littermates to assess their role in anti-glomerular basement membrane-induced glomerulonephritis. Following administration of anti-glomerular basement membrane Abs, W/W(v) mice exhibited increased mortality as compared with +/+ mice owing to rapid deterioration of renal function. Reconstitution of the mast cell population in W/W(v) mice restored protection. This was independent of activating FcgammaR, as protection was also obtained using mast cells deficient in FcRgamma. Comparative histological analysis of kidneys showed that deterioration of renal function was caused by the presence of thick layers of subendothelial glomerular deposits in W/W(v) mice, while +/+ mice or mast cell-reconstituted W/W(v) mice showed significantly less. Deposits appeared during the early phase of disease and persisted thereafter, and were accompanied by enhanced macrophage recruitment. Immunohistochemical analysis revealed increased amounts of fibrin and type I collagen in W/W(v) mice, which were also unable to maintain high tissue plasminogen activator and urinary-type plasminogen activator activity in urine in the heterologous phase of disease. Our results indicate that mast cells by their ability to mediate remodeling and repair functions are protective in immune complex-mediated glomerulonephritis.
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Affiliation(s)
- Yutaka Kanamaru
- INSERM Unité 699, Faculté de Médecine X, Bichat Medical School, 16 rue Henri Huchard, 75780 Paris Cedex 18, France
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Zhang SX, Wang JJ, Lu K, Mott R, Longeras R, Ma JX. Therapeutic potential of angiostatin in diabetic nephropathy. J Am Soc Nephrol 2006; 17:475-86. [PMID: 16394111 DOI: 10.1681/asn.2005020217] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Angiostatin is a proteolytic fragment of plasminogen and a potent angiogenic inhibitor. Previous studies have shown that angiostatin inhibits retinal neovascularization and reduces retinal vascular permeability in diabetic retinopathy. Here, it is reported for the first time that angiostatin is also implicated in diabetic nephropathy (DN). Angiostatin levels are dramatically decreased in the kidney of streptozotocin-induced diabetic rats. Consistently, diabetic kidneys also showed decreased expression and proteolytic activities of matrix metalloproteinase-2, an enzyme that releases angiostatin from plasminogen. Adenovirus-mediated delivery of angiostatin significantly alleviated albuminuria and attenuated the glomerular hypertrophy in diabetic rats. Moreover, angiostatin treatment downregulated the expression of vascular endothelial growth factor and TGF-beta1, two major pathogenic factors of DN, in diabetic kidneys. In cultured human mesangial cells, angiostatin blocked the overexpression of vascular endothelial growth factor and TGF-beta1 that were induced by high glucose while increasing the levels of pigment epithelium-derived factor, an endogenous inhibitor of DN. Moreover, angiostatin effectively inhibited the high-glucose-and TGF-beta1-induced overproduction of proinflammatory factors and extracellular matrix proteins via blockade of the Smad signaling pathway. These findings suggest that the decrease of angiostatin levels in diabetic kidney may contribute to the pathologic changes such as inflammation and fibrosis in DN. Therefore, angiostatin has therapeutic potential in DN as a result of its anti-inflammatory and antifibrosis activities.
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Affiliation(s)
- Sarah X Zhang
- Department of Medicine Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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27
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Rogier E, Durrbach A, Abecassis L, Ferlicot S, Snanoudj R, Baudreuil S, Arzouk N, Vazquez A, Charpentier B, Bourgeade MF. A novel biological assay to detect the active form of TGF-beta in urine to monitor renal allograft rejection. Kidney Int 2005; 68:1875-83. [PMID: 16164666 DOI: 10.1111/j.1523-1755.2005.00607.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Transforming growth factor-beta (TGF-beta) plays an important role in renal fibrosis. Measurement of the concentration of the active form of TGF-beta particularly in urine may help our understanding of the mechanism of chronic allograft nephropathy and could be used as a diagnostic tool. However, TGF-beta release and activation are complex and, consequently, there is currently no accurate way to measure TGF-beta activity. METHODS TGF-beta-sensitive BL41 cells were stably transfected with a reporter plasmid harboring a synthetic TGF-beta-inducible DNA sequence upstream from the luciferase gene. Cells were incubated with urine samples from normal donors or transplanted recipients with or without patent nephropathy, and the active form of TGF-beta was determined as luciferase activity. RESULTS We have established a cell line which expresses luciferase activity in response to active TGF-beta in a dose-dependent manner. Moreover, the use of a histone deacetylase inhibitor greatly increased sensitivity to TGF-beta and also stabilized luciferase inductibility. This test is highly specific to active TGF-beta. Detectable levels of TGF-beta were found in urine from patients with renal dysfunction due to acute or chronic renal allograft rejection (P < 0.001), but not in that from patients with stable, correctly functional kidneys. CONCLUSION We describe a highly sensitive and specific assay for active TGF-beta. We also show that, in cases of renal allograft, TGF-beta expression is highly and significantly correlated with acute or chronic rejections.
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Affiliation(s)
- Edith Rogier
- INSERM Unité 542, Hôpital Paul Brousse, Villejuif, France
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Abstract
New therapeutic approaches are needed to address the current epidemic of chronic kidney disease. Beyond delaying the inevitable onset of end-stage kidney disease the ultimate dream of clinical therapy is disease regression. Degradation of the interstitial matrix proteins is potentially feasible, especially before the interstitial "scar" becomes highly organized. Currently the specific matrix-degrading proteases that perform this function in vivo have not been clearly identified although several candidates have been suggested. Reversing renal fibrosis will also mandate removal of interstitial myofibroblasts that are the major source of the fibrosis-associated interstitial matrix proteins. However, the greater therapeutic challenge pertains to the current inability to regenerate intact functional nephrons in a site where they have been destroyed. In chronic tubulointerstitial damage that typifies all progressive kidney diseases, it is not interstitial matrix accumulation per se that leads to renal functional decline but rather its destructive effects on neighboring cells. In particular, loss of peritubular capillaries and tubules are the morphological features that underlie declining renal function. Recent advances in several basic scientific fields of investigation such as matrix biology, developmental biology, angiogenesis, and stem cell biology have identified new candidate therapeutic targets. A powerful new molecular tool-box is at our disposal that can be used to begin to translate recent discoveries into the clinical research arena with the goal of reversing renal fibrosis in a functionally meaningful way.
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Wang JJ, Zhang SX, Lu K, Chen Y, Mott R, Sato S, Ma JX. Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy. Diabetes 2005; 54:243-50. [PMID: 15616035 DOI: 10.2337/diabetes.54.1.243] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-beta (TGF-beta) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the high-glucose-induced overexpression of TGF-beta, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-beta expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy.
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Affiliation(s)
- Joshua J Wang
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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