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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [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: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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Romero-Márquez JM, Badillo-Carrasco A, Navarro-Hortal MD, Rivas-García L, Jiménez-Trigo V, Varela-López A. Nutritional interventions based on dietary restriction and nutrient reductions for the prevention of doxorubicin chemotherapy side effects. MEDITERRANEAN JOURNAL OF NUTRITION AND METABOLISM 2021. [DOI: 10.3233/mnm-210020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: Doxorubicin (DOX) is one of most used chemotherapeutic drugs, but it has important adverse effects. Nutrition has a critical role to prevent or minimize chemotherapy side effects. Caloric and nutrient restriction has been widely studied in different health fields showing extensive beneficial effects. Given the importance of these interventions, it is expected that some of them have benefits in patients under DOX chemotherapy. OBJECTIVE: This review aimed to compile published studies evaluating the effects of different dietary intetrventions based on restriction of calories or certain nutrients against DOX-induced damage and toxicity. RESULTS: Caloric restriction and partial reduction of fat have shown to reduce DOX cardiotoxicity correlating with a reduction of oxidative stress. Reduction of dietary fat was proved to act in the same sense at liver and kidney. Studies in relation to protein reduction is more elevated has focused only on kidneys and bone, and under certain circumstances, these interventions could increase susceptibility to DOX toxicity. CONCLUSIONS: The promising effects of restriction of dietary fat, protein and sodium on differerent organs have been supported by a greater number of studies among all the dietary interventions evaluated. Still, clinical studies are necessary to confirm the potential usefulness of these interventions.
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Affiliation(s)
- Jose M. Romero-Márquez
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
| | - Alberto Badillo-Carrasco
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
| | - María D. Navarro-Hortal
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
| | - Lorenzo Rivas-García
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
| | - Victoria Jiménez-Trigo
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
| | - Alfonso Varela-López
- Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Avda del Conocimiento sn., 18100 Armilla, Granada, Spain
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Opazo-Ríos L, Mas S, Marín-Royo G, Mezzano S, Gómez-Guerrero C, Moreno JA, Egido J. Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities. Int J Mol Sci 2020; 21:E2632. [PMID: 32290082 PMCID: PMC7177360 DOI: 10.3390/ijms21072632] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
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Affiliation(s)
- Lucas Opazo-Ríos
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Sebastián Mas
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Gema Marín-Royo
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Sergio Mezzano
- Laboratorio de Nefrología, Facultad de Medicina, Universidad Austral de Chile, 5090000 Valdivia, Chile;
| | - Carmen Gómez-Guerrero
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
| | - Juan Antonio Moreno
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, 14004 Cordoba, Spain
- Hospital Universitario Reina Sofía, 14004 Cordoba, Spain
| | - Jesús Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040 Madrid, Spain; (L.O.-R.); (G.M.-R.); (C.G.-G.); (J.E.)
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Li XY, Chen HR, Zha XQ, Chen S, Pan LH, Li QM, Luo JP. Prevention and possible mechanism of a purified Laminaria japonica polysaccharide on adriamycin-induced acute kidney injury in mice. Int J Biol Macromol 2020; 148:591-600. [PMID: 31958563 DOI: 10.1016/j.ijbiomac.2020.01.159] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 12/26/2019] [Accepted: 01/16/2020] [Indexed: 12/14/2022]
Abstract
The present work aims to investigate the effects and underlying mechanism of a homogeneous Laminaria japonica polysaccharide (LJP61A) on acute kidney injury (AKI) in mice. According to the results of biochemical and pathological analysis, we concluded that LJP61A could protect kidney from the damage of adriamycin in AKI mice. Compared to the model group, the mRNA level of cytokines (TNF-α, IL-1β and MCP-1) and protein level of mesenchymal markers demsin were decrease by the treatment of LJP61A while the protein levels of podocyte structure markers (Nephrin and WT-1) were increased. Moreover, the adriamycin-induced enhancement of phosphor-p65, phosphor-p38, phosphor-ERK1/2 and phosphor-JNK in the kidney of AKI mice were significantly suppressed by LJP61A. Similar variation was observed in the mRNA and protein levels of TGF-β1 and Smad3. These results suggested that LJP61A prevented acute kidney injury possibly via regulating TGF-β1-mediated Smad3, MAPKs and NF-κB signaling pathways.
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Affiliation(s)
- Xue-Ying Li
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China; School of Food and Biological Engineering, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Hao-Ran Chen
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Xue-Qiang Zha
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China; School of Food and Biological Engineering, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China; Key Laboratory of Metabolism and Regulation for Major Disease of Anhui Higher Education Institutes, Hefei University of Technology, People's Republic of China.
| | - Shun Chen
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China; School of Food and Biological Engineering, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Li-Hua Pan
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Qiang-Ming Li
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Jian-Ping Luo
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China; School of Food and Biological Engineering, Hefei University of Technology, No 193 Tunxi Road, Hefei 230009, People's Republic of China.
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Comparative Study of Fucoidan from Saccharina japonica and Its Depolymerized Fragment on Adriamycin-Induced Nephrotic Syndrome in Rats. Mar Drugs 2020; 18:md18030137. [PMID: 32120786 PMCID: PMC7142486 DOI: 10.3390/md18030137] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 02/23/2020] [Accepted: 02/25/2020] [Indexed: 12/26/2022] Open
Abstract
Nephrotic syndrome (NS) is a clinical syndrome with a variety of causes, mainly characterized by heavy proteinuria, hypoalbuminemia, and edema. At present, identification of effective and less toxic therapeutic interventions for nephrotic syndrome remains to be an important issue. In this study, we isolated fucoidan from Saccharina japonica and prepared its depolymerized fragment by oxidant degradation. Fucoidan and its depolymerized fragment had similar chemical constituents. Their average molecular weights were 136 and 9.5 kDa respectively. The effect of fucoidan and its depolymerized fragment on adriamycin-induced nephrotic syndrome were investigated in a rat model. The results showed that adriamycin-treated rats had heavy proteinuria and increased blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC), and total triglyceride (TG) levels. Oral administration of fucoidan or low-molecular-weight fucoidan for 30 days could significantly inhibit proteinuria and decrease the elevated BUN, SCr, TG, and TC level in a dose-dependent manner. At the same dose (100 mg/kg), low-molecular-weight fucoidan had higher renoprotective activity than fucoidan. Their protective effect on nephrotic syndrome was partly related to their antioxidant activity. The results suggested that both fucoidan and its depolymerized fragment had excellent protective effect on adriamycin-induced nephrotic syndrome, and might have potential for the treatment of nephrotic syndrome.
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Effect of Poria cocos on Puromycin Aminonucleoside-Induced Nephrotic Syndrome in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:570420. [PMID: 25165480 PMCID: PMC4140122 DOI: 10.1155/2014/570420] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 07/08/2014] [Accepted: 07/13/2014] [Indexed: 01/26/2023]
Abstract
Nephrotic syndrome is associated with altered renal handling of water and sodium and changes in the levels of aquaporins (AQPs) and epithelial Na channels (ENaCs). The dried sclerotia of Poria cocos Wolf (WPC) have been used for treating chronic edema and nephrosis. We evaluated the effects of WPC on puromycin aminonucleoside- (PAN-) induced renal functional derangement and altered renal AQP2 and ENaC expression. In the nephrotic syndrome rat model, animals were injected with 75 mg/kg PAN and then treated with Losartan (30 mg·kg−1·day−1) or WPC (200 mg·kg−1·day−1) for 7 days. In the WPC group, proteinuria and ascites improved significantly. Plasma levels of triglyceride, total cholesterol, and low-density lipoprotein- (LDL-) cholesterol reduced significantly in the WPC group. In addition, the WPC group exhibited attenuation of the PAN-induced increase in AQP2 and ENaC α/β subunit protein and mRNA levels. WPC suppressed significantly PAN-induced organic osmolyte regulators, reducing serum- and glucocorticoid-inducible protein kinase (Sgk1) and sodium-myo-inositol cotransporter (SMIT) mRNA expression. Our results show that WPC improves nephrotic syndrome, including proteinuria and ascites, through inhibition of AQP2 and ENaC expression. Therefore, WPC influences body-fluid regulation via inhibition of water and sodium channels, thereby, improving renal disorders such as edema or nephrosis.
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Desai VG, Herman EH, Moland CL, Branham WS, Lewis SM, Davis KJ, George NI, Lee T, Kerr S, Fuscoe JC. Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F1 mouse model. Toxicol Appl Pharmacol 2012; 266:109-21. [PMID: 23142469 DOI: 10.1016/j.taap.2012.10.025] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2012] [Revised: 10/05/2012] [Accepted: 10/12/2012] [Indexed: 10/27/2022]
Abstract
Serum levels of cardiac troponins serve as biomarkers of myocardial injury. However, troponins are released into the serum only after damage to cardiac tissue has occurred. Here, we report development of a mouse model of doxorubicin (DOX)-induced chronic cardiotoxicity to aid in the identification of predictive biomarkers of early events of cardiac tissue injury. Male B6C3F(1) mice were administered intravenous DOX at 3mg/kg body weight, or an equivalent volume of saline, once a week for 4, 6, 8, 10, 12, and 14weeks, resulting in cumulative DOX doses of 12, 18, 24, 30, 36, and 42mg/kg, respectively. Mice were sacrificed a week following the last dose. A significant reduction in body weight gain was observed in mice following exposure to a weekly DOX dose for 1week and longer compared to saline-treated controls. DOX treatment also resulted in declines in red blood cell count, hemoglobin level, and hematocrit compared to saline-treated controls after the 2nd weekly dose until the 8th and 9th doses, followed by a modest recovery. All DOX-treated mice had significant elevations in cardiac troponin T concentrations in plasma compared to saline-treated controls, indicating cardiac tissue injury. Also, a dose-related increase in the severity of cardiac lesions was seen in mice exposed to 24mg/kg DOX and higher cumulative doses. Mice treated with cumulative DOX doses of 30mg/kg and higher showed a significant decline in heart rate, suggesting drug-induced cardiac dysfunction. Altogether, these findings demonstrate the development of DOX-induced chronic cardiotoxicity in B6C3F(1) mice.
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Affiliation(s)
- Varsha G Desai
- Personalized Medicine Branch, Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
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Effects of dietary protein and fat contents on renal function and inflammatory cytokines in rats with adriamycin-induced nephrotic syndrome. Mediators Inflamm 2011; 2011:945123. [PMID: 21822358 PMCID: PMC3136151 DOI: 10.1155/2011/945123] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 03/03/2011] [Indexed: 11/18/2022] Open
Abstract
The effects of dietary protein and fat on renal function-related blood and urine parameters, such as albumin, urinary protein,and inflammatory cytokines were investigated in adriamycin- (ADR) induced nephrotic syndrome rats. ADR (2 mg/kg BW) was injected i.p. weekly for six weeks to develop nephrotic syndrome; thereafter rats were fed low-protein/high-fat (LPHF) or high-protein/low-fat (HPLF) diets for five weeks. Renal function-related blood and urine parameters were measured before and after dietary intervention. Serum levels of albumin, TG, and creatinine were significantly higher in the LPHF group than in the HPLF group. Serum levels of albumin were low and urinary protein excretion protein was high in HPLF group. BUN and UUN levels were higher in the HPLF group than in the LPHF. Urinary excretion of creatinine was significantly higher in the HPLF group than in the LPHF group. Serum inflammatory cytokine levels did not differ between the two groups, however the levels of IL-6, TNF-α, and IL-13 in splenocyte supernatants were significantly higher in the LPHF group than in the HPLF group. We confirmed that protein and fat contents in diet affect renal function-related blood and urine parameters and splenocyte inflammatory cytokine levels in ADR-induced nephrotic syndrome rats.
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Pippin JW, Brinkkoetter PT, Cormack-Aboud FC, Durvasula RV, Hauser PV, Kowalewska J, Krofft RD, Logar CM, Marshall CB, Ohse T, Shankland SJ. Inducible rodent models of acquired podocyte diseases. Am J Physiol Renal Physiol 2009; 296:F213-29. [DOI: 10.1152/ajprenal.90421.2008] [Citation(s) in RCA: 193] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Glomerular diseases remain the leading cause of chronic and end-stage kidney disease. Significant advances in our understanding of human glomerular diseases have been enabled by the development and better characterization of animal models. Diseases of the glomerular epithelial cells (podocytes) account for the majority of proteinuric diseases. Rodents have been extensively used experimentally to better define mechanisms of disease induction and progression, as well as to identify potential targets and therapies. The development of podocyte-specific genetically modified mice has energized the research field to better understand which animal models are appropriate to study acquired podocyte diseases. In this review we discuss inducible experimental models of acquired nondiabetic podocyte diseases in rodents, namely, passive Heymann nephritis, puromycin aminonucleoside nephrosis, adriamycin nephrosis, liopolysaccharide, crescentic glomerulonephritis, and protein overload nephropathy models. Details are given on the model backgrounds, how to induce each model, the interpretations of the data, and the benefits and shortcomings of each. Genetic rodent models of podocyte injury are excluded.
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Miller B, Patel VA, Sorokin A. Cyclooxygenase-2 rescues rat mesangial cells from apoptosis induced by adriamycin via upregulation of multidrug resistance protein 1 (P-glycoprotein). J Am Soc Nephrol 2006; 17:977-85. [PMID: 16540558 DOI: 10.1681/asn.2005101076] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Cyclooxygenase-2 (COX-2) is constitutively expressed in restricted subpopulations of kidney cells, where it presumably acts as an antiapoptotic factor. In conditions that are characterized by inflammation, COX-2 expression also has been described in glomerular mesangial cells (GMC), where COX-2 is not expressed constitutively. It was shown previously that adenovirus-mediated gene transfer of COX-2 into rat GMC led to increased expression and activity of multidrug resistance protein 1 (MDR-1), a membrane transporter that functions as an efflux pump for chemotherapeutic drugs, including Adriamycin (ADR). In ADR nephrotoxicity, a pathologic change in glomeruli could be partially explained by ADR-mediated changes in GMC. Here it is demonstrated that ADR (also known as doxorubicin; 1 microg/ml) induced apoptosis in 15.3 +/- 2.2% of GMC, whereas after adenovirus-mediated COX-2 expression, only 6.6 +/- 0.4% of ADR-treated cells underwent apoptosis. This protective effect was nullified by treatment with NS398, specific COX-2 inhibitor. ADR efflux is greater in COX-2-overexpressing cells, when compared with control, which is attributed to the increased MDR-1 expression. Addition of PSC833, the specific MDR-1 inhibitor, completely abolished the protective effect of COX-2 overexpression and increased the level of apoptosis in GMC that were exposed to ADR. These data suggest that COX-2 protects GMC from ADR-mediated apoptosis via transcriptional upregulation of MDR-1 and that induced COX-2 expression would lessen ADR nephrotoxicity.
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Affiliation(s)
- Bradley Miller
- Department of Medicine, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
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Abstract
The realization that the adult nervous system develops from multipotential stem cells and that cells with stem-like properties are retained in the adult CNS has provoked an intense search for ways to utilize their potential for therapeutic treatments of multiple neurological disorders. Transplantation of neural stem cells or more restricted progenitors to replace cells lost to injury or disease may facilitate functional recovery in a spectrum of neurological disorders. Alternatively, expansion and recruitment of endogenous progenitors may be effective in treating widespread cell loss in the adult CNS. A major challenge to the development of effective stem cell therapies is to direct the fate of the newly generated cells to specifically replace those lost to disease. Insights from developmental research are providing molecular targets for regulating the differentiation of neural stem cells and their progeny in areas of injury to the adult CNS. Given the commonality of processes mediating the assembly of multicellular systems, the approaches developed in the CNS will likely be applicable for selective cell replacement in the auditory system.
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Affiliation(s)
- Robert H Miller
- Department of Neurosciences, Center for Stem Cell and Regenerative Medicine, Case School of Medicine Cleveland, OH 44106, USA.
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Pedrycz A, Wieczorski M, Czerny K. Late effects of adriamycin single dose on fetal rat kidney-ultrastructural assessment. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2005; 20:157-160. [PMID: 21783583 DOI: 10.1016/j.etap.2004.12.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2004] [Accepted: 12/12/2004] [Indexed: 05/31/2023]
Abstract
The purpose of the study was ultrastructural evaluation of long-lasting activity of an antibiotic from anthracycline group-adriamycin (ADR), on fetal kidneys from rat females which 4 weeks before fertilization were given a single dose of adriamycin intraperitoneally. The results showed the damage of glomerular filtration barrier (fusion of podocytes' foot processes) and degenerative lesions in tubular epithelial cells (EC). Those changes were described in literature in the case of adriamycin induced nephrotic syndrome in adult rats. If those lesions are due to increased glomerular permeability for proteins or cytotoxic activity of adriamycin can be decided after further biochemical tests of fetal urine and blood.
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Affiliation(s)
- Agnieszka Pedrycz
- Department of Histology and Embryology Medical University of Lublin, Ul. Leonarda 5/34, 20-625 Lublin, Poland
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Buzello M, Haas CS, Hauptmann F, Gross ML, Faulhaber J, Schultze-Mosgau S, Ehmke H, Ritz E, Amann K. No aggravation of renal injury in apolipoprotein E knockout mice (ApoE(-/-)) after subtotal nephrectomy. Nephrol Dial Transplant 2004; 19:566-73. [PMID: 14767010 DOI: 10.1093/ndt/gfg578] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND There is substantial experimental evidence that various forms of dyslipidaemia aggravate the course of renal failure and that reversal of dyslipidaemia ameliorates progression of renal failure. The apolipoprotein E knockout mouse (ApoE(-/-)) is an established model of accelerated atherogenesis. We investigated whether the course of renal disease after uninephrectomy (UNX) and subtotal nephrectomy (SNX) is altered in ApoE(-/-) mice compared with their genetic controls. METHODS Ten-week-old, male ApoE(-/-) mice (body weight 25+/-2 g) were subjected either to sham operation (sham), UNX or SNX. C57BL/6 sham, UNX and SNX mice served as controls (body weight 26+/-3 g). The food intake of ApoE(-/-) and C57BL/6 mice was kept identical by a pair-feeding protocol. After 12 weeks, mean arterial blood pressure and heart rate were measured in awake resting mice, the kidneys were perfusion fixed and analysed using quantitative histological methods, immunohistochemistry and RT-PCR. RESULTS At baseline, the sham ApoE(-/-) mice had significantly higher (P<0.05) serum cholesterol and triglycerides than the controls. In parallel, mean arterial blood pressure was significantly elevated in sham ApoE(-/-) mice compared with controls (137+/-15 vs 116+/-4 mmHg; P<0.05). In the sham groups, the glomerulosclerosis index was significantly higher in the ApoE(-/-) mice (1.05+/-0.14 vs 0.57+/-0.07; P<0.05), whereas the tubulointerstitial damage score was comparable (0.06+/-0.04 vs 0.04+/-0.02; n.s.). After SNX there was a significant increase in glomerulosclerosis index, but no difference could be detected between ApoE(-/-) and controls (1.75+/-0.16 vs 1.61+/-0.01, n.s.). The same was true for the tubulointerstitial damage index. CONCLUSIONS Despite some glomerulosclerosis and elevated mean arterial blood pressure at baseline, no acceleration of progression of renal disease was found in this genetic model of hyperlipoproteinaemia. This observation suggests that despite the known spontaneous histological changes in untouched kidneys, however, the presence of hyperlipidaemia in the ApoE(-/-) mouse does not cause more severe progression in the present models of moderate renal disease.
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Affiliation(s)
- Moriz Buzello
- Department of Pathology, University of Heidelberg, Germany
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Okuno S, Kondo M, Yamasaki Y, Miyao H, Ono T, Iwanaga T, Omori K, Okano M, Suzuki M, Momota H, Hishigaki H, Hayashi I, Goto Y, Shinomiya H, Harada Y, Hirashima T, Kanemoto N, Asai T, Wakitani S, Takagi T, Nakamura Y, Tanigami A, Watanabe TK. Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats. Diabetes Obes Metab 2002; 4:309-18. [PMID: 12190994 DOI: 10.1046/j.1463-1326.2002.00217.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome. METHODS Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls. RESULTS Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05). CONCLUSION Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.
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Affiliation(s)
- S Okuno
- Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Kawauchi-cho, Tokushima, Japan
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Wellington CL, Walker EKY, Suarez A, Kwok A, Bissada N, Singaraja R, Yang YZ, Zhang LH, James E, Wilson JE, Francone O, McManus BM, Hayden MR. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. J Transl Med 2002; 82:273-83. [PMID: 11896206 DOI: 10.1038/labinvest.3780421] [Citation(s) in RCA: 232] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Mutations in ABCA1 cause the allelic disorders familial hypolipoproteinemia and Tangier Disease. To identify where ABCA1 was likely to have a functional role, we determined the cellular and tissue-specific patterns of murine ABCA1 expression. RT-PCR and Western blot analysis on dissected murine tissues demonstrated broad expression of ABCA1 mRNA and protein in many tissues with prominent protein expression in liver, testis, and adrenal tissue. In situ hybridization and immunohistochemistry experiments demonstrated specific patterns of ABCA1 expression at the cellular level, with hepatocytes, the epithelial lining of the digestive system and bladder, the proximal convoluted tubule of the kidney, and Purkinje and cortical pyramidal neurons containing abundant ABCA1 protein. Significant discordance between relative mRNA and protein expression patterns suggests the possibility of post-transcriptional regulation of ABCA1 expression in selected cells or tissues. We also show that ABCA1 protein levels are up-regulated specifically in the liver after exposure to an atherogenic diet for 7 days, supporting a major role for the liver in dietary modulation of HDL-C levels. Our observations show that ABCA1 is expressed in a pattern consistent with its role in HDL-C metabolism. Additionally, ABCA1 may have important functional roles in other cell types independent of HDL-C regulation.
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Affiliation(s)
- Cheryl L Wellington
- Centre for Molecular Medicine and Therapeutics, St. Paul's Hospital/Providence Health Care-University of British Columbia, Canada
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