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Liu R, Juncos LA, Lu Y, Wei J, Zhang J, Wang L, Lai EY, Carlstrom M, Persson AEG. The Role of Macula Densa Nitric Oxide Synthase 1 Beta Splice Variant in Modulating Tubuloglomerular Feedback. Compr Physiol 2023; 13:4215-4229. [PMID: 36715280 PMCID: PMC9990375 DOI: 10.1002/cphy.c210043] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Abnormalities in renal electrolyte and water excretion may result in inappropriate salt and water retention, which facilitates the development and maintenance of hypertension, as well as acid-base and electrolyte disorders. A key mechanism by which the kidney regulates renal hemodynamics and electrolyte excretion is via tubuloglomerular feedback (TGF), an intrarenal negative feedback between tubules and arterioles. TGF is initiated by an increase of NaCl delivery at the macula densa cells. The increased NaCl activates luminal Na-K-2Cl cotransporter (NKCC2) of the macula densa cells, which leads to activation of several intracellular processes followed by the production of paracrine signals that ultimately result in a constriction of the afferent arteriole and a tonic inhibition of single nephron glomerular filtration rate. Neuronal nitric oxide (NOS1) is highly expressed in the macula densa. NOS1β is the major splice variant and accounts for most of NO generation by the macula densa, which inhibits TGF response. Macula densa NOS1β-mediated modulation of TGF responses plays an essential role in control of sodium excretion, volume and electrolyte hemostasis, and blood pressure. In this article, we describe the mechanisms that regulate macula densa-derived NO and their effect on TGF response in physiologic and pathologic conditions. © 2023 American Physiological Society. Compr Physiol 13:4215-4229, 2023.
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Affiliation(s)
- Ruisheng Liu
- Department of Molecular Pharmacology & Physiology
- Hypertension and Kidney Research Center, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Luis A. Juncos
- Department of Internal Medicine, Central Arkansas Veterans Healthcare System, Little Rock, AR
| | - Yan Lu
- Division of Nephrology, University of Alabama at Birmingham, Birmingham AL
| | - Jin Wei
- Department of Molecular Pharmacology & Physiology
| | - Jie Zhang
- Department of Molecular Pharmacology & Physiology
| | - Lei Wang
- Department of Molecular Pharmacology & Physiology
| | - En Yin Lai
- Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China
| | - Mattias Carlstrom
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - A. Erik G Persson
- Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
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Potential Roles of Anti-Inflammatory Plant-Derived Bioactive Compounds Targeting Inflammation in Microvascular Complications of Diabetes. Molecules 2022; 27:molecules27217352. [PMID: 36364178 PMCID: PMC9657994 DOI: 10.3390/molecules27217352] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders, the characteristics of which include chronic hyperglycemia owing to defects in insulin function, insulin secretion, or both. Inflammation plays a crucial role in DM pathogenesis and innate immunity in the development of microvascular complications of diabetes. In addition, hyperglycemia and DM mediate a proinflammatory microenvironment that can result in various microvascular complications, including diabetic nephropathy (DNP), diabetic neuropathy (DN), and diabetic retinopathy (DR). DNP is a major cause of end-stage renal disease. DNP can lead to albuminuria, decreased filtration, mesangium expansion, thickening of the basement membrane, and eventually renal failure. Furthermore, inflammatory cells can accumulate in the interstitium and glomeruli to deteriorate DNP. DN is another most prevalent microvascular complication of DM and the main cause of high mortality, disability, and a poor quality of life. DNs have a wide range of clinical manifestations because of the types of fiber dysfunctions and complex structures of the peripheral nervous system. DR is also a microvascular and multifactorial disease, as well as a major cause of visual impairment globally. Pathogenesis of DR is yet to be fully revealed, however, numerous studies have already confirmed the role of inflammation in the onset and advancement of DR. Despite evidence, and better knowledge regarding the pathogenesis of these microvascular complications of diabetes, there is still a deficiency of effective therapies. Bioactive compounds are mainly derived from plants, and these molecules have promising therapeutic potential. In this review, evidence and molecular mechanisms regarding the role of inflammation in various microvascular complications of diabetes including DNP, DN, and DR, have been summarized. The therapeutic potential of several bioactive compounds derived from plants in the treatment of these microvascular complications of diabetes has also been discussed.
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Hernandez-Diaz I, Pan J, Ricciardi CA, Bai X, Ke J, White KE, Flaquer M, Fouli GE, Argunhan F, Hayward AE, Hou FF, Mann GE, Miao RQ, Long DA, Gnudi L. Overexpression of Circulating Soluble Nogo-B Improves Diabetic Kidney Disease by Protecting the Vasculature. Diabetes 2019; 68:1841-1852. [PMID: 31217174 PMCID: PMC6706276 DOI: 10.2337/db19-0157] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 06/10/2019] [Indexed: 12/12/2022]
Abstract
Damage to the vasculature is the primary mechanism driving chronic diabetic microvascular complications such as diabetic nephropathy, which manifests as albuminuria. Therefore, treatments that protect the diabetic vasculature have significant therapeutic potential. Soluble neurite outgrowth inhibitor-B (sNogo-B) is a circulating N-terminus isoform of full-length Nogo-B, which plays a key role in vascular remodeling following injury. However, there is currently no information on the role of sNogo-B in the context of diabetic nephropathy. We demonstrate that overexpression of sNogo-B in the circulation ameliorates diabetic kidney disease by reducing albuminuria, hyperfiltration, and abnormal angiogenesis and protecting glomerular capillary structure. Systemic sNogo-B overexpression in diabetic mice also associates with dampening vascular endothelial growth factor-A signaling and reducing endothelial nitric oxide synthase, AKT, and GSK3β phosphorylation. Furthermore, sNogo-B prevented the impairment of tube formation, which occurred when human endothelial cells were exposed to sera from patients with diabetic kidney disease. Collectively, these studies provide the first evidence that sNogo-B protects the vasculature in diabetes and may represent a novel therapeutic target for diabetic vascular complications.
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Affiliation(s)
- Ivan Hernandez-Diaz
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Jiaqi Pan
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Carlo Alberto Ricciardi
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Xiaoyan Bai
- Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jianting Ke
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Kathryn E White
- Electron Microscopy Unit, Newcastle University, Newcastle upon Tyne, U.K
| | - Maria Flaquer
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Georgia E Fouli
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Fulye Argunhan
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Anthea E Hayward
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | - Fan Fan Hou
- Division of Nephrology, State Key Laboratory of Organ Failure Research, National Clinical Research Center for Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Giovanni E Mann
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K
| | | | - David A Long
- Developmental Biology and Cancer Programme, Great Ormond Street Institute of Child Health, University College London, London, U.K
| | - Luigi Gnudi
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, King's College London, London, U.K.
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Hwang JY, Kan WC, Liu YB, Chuang LY, Guh JY, Yang YL, Huang JS. Angiotensin-converting enzyme inhibitors attenuated advanced glycation end products-induced renal tubular hypertrophy via enhancing nitric oxide signaling. J Cell Physiol 2019; 234:17473-17481. [PMID: 30825199 DOI: 10.1002/jcp.28369] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 12/20/2018] [Accepted: 12/21/2018] [Indexed: 12/19/2022]
Abstract
Advanced glycation end products (AGE) and angiotensin II were closely correlated with the progression of diabetic nephopathy (DN). Nitric oxide (NO) is a protective mediator of renal tubular hypertrophy in DN. Here, we examined the molecular mechanisms of angiotensin-converting enzyme inhibitor (ACEI) and NO signaling responsible for diminishing AGE-induced renal tubular hypertrophy. In human renal proximal tubular cells, AGE decreased NO production, inducible NOS activity, guanosine 3',5'-cyclic monophosphate (cGMP) synthesis, and cGMP-dependent protein kinase (PKG) activation. All theses effects of AGE were reversed by treatment with ACEIs (captopril and enalapril), the NO donor S-nitroso-N-acetylpenicillamine (SNAP), and the PKG activator 8-para-chlorophenylthio-cGMPs (8-pCPT-cGMPs). In addition, AGE-enhanced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) were clearly reduced by captopril, enalapril, SNAP, and 8-pCPT-cGMPs. The abilities of ACEIs and NO/PKG activation to inhibit AGE-induced hypertrophic growth were verified by the observation that captopril, enalapril, SNAP, and 8-pCPT-cGMPs decreased protein levels of fibronectin, p21 Waf1/Cip1 , and receptor for AGE. The results of the present study suggest that ACEIs significantly reduced AGE-increased ERK/JNK/p38 MAPK activation and renal tubular hypertrophy partly through enhancement of the NO/PKG pathway.
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Affiliation(s)
- Jean-Yu Hwang
- Department of Food Nutrition, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC
| | - Wei-Chih Kan
- Department of Internal Medicine, Division of Nephology, Chi-Mei Medical Center, Tainan, Taiwan, ROC.,Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC
| | - Yao-Bin Liu
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC
| | - Lea-Yea Chuang
- Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Jinn-Yuh Guh
- Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC
| | - Yu-Lin Yang
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC
| | - Jau-Shyang Huang
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan, ROC
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Kaur R, Sodhi RK, Aggarwal N, Kaur J, Jain UK. Renoprotective effect of lansoprazole in streptozotocin-induced diabetic nephropathy in wistar rats. Naunyn Schmiedebergs Arch Pharmacol 2015; 389:73-85. [PMID: 26475618 DOI: 10.1007/s00210-015-1182-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 10/06/2015] [Indexed: 01/11/2023]
Abstract
Proton pump inhibitors (PPIs) have exhibited glucose lowering action in animal models of diabetes; however, their potential in diabetes-related complications has not yet been evaluated. Hence, the present study has been undertaken to investigate the renoprotective potential of lansoprazole in streptozotocin-induced diabetic nephropathy in wistar rats. Diabetic nephropathy was induced with a single injection of streptozotocin (STZ, 45 mg/kg, i.p.). Lansoprazole (40 mg/kg; 80 mg/kg, p.o.; 4 weeks) was administered to diabetic rats after 4 weeks of STZ treatment. A battery of biochemical tests such as serum glucose, glycated hemoglobin, blood urea nitrogen (BUN), serum creatinine, albumin, and kidney weight/body weight (%) ratio were performed to evaluate the renal functions. Oxidative stress was determined by estimating renal thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) levels. Lipid profile was assessed by determining serum cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL). The STZ-treated rats demonstrated deleterious alterations in kidney functions, enhanced oxidative stress, and disturbed lipid profile. Administration of lansoprazole to diabetic rats significantly reduced serum glucose, glycated hemoglobin, BUN, creatinine, albumin levels, and oxidative stress. Serum lipids like TC and TG were decreased, and HDL was enhanced in lansoprazole-treated STZ rats. The findings of our study indicate that renoprotective effects of lansoprazole may be attributed to its glucose-lowering, lipid-lowering, and antioxidative potential.
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Mitrou N, Morrison S, Mousavi P, Braam B, Cupples WA. Transient impairment of dynamic renal autoregulation in early diabetes mellitus in rats. Am J Physiol Regul Integr Comp Physiol 2015; 309:R892-901. [DOI: 10.1152/ajpregu.00247.2015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/31/2015] [Indexed: 01/01/2023]
Abstract
Renal autoregulation is impaired in early (1 wk) diabetes mellitus (DM) induced by streptozotocin, but effective in established DM (4 wk). Furthermore nitric oxide synthesis (NOS) inhibition with NG-nitro-l-arginine methyl ester (l-NAME) significantly improved autoregulation in early DM but not in established DM. We hypothesized that autoregulation is transiently impaired in early DM because of increased NO availability in the kidney. Because of the conflicting evidence available for a role of NO in DM, we tested the hypothesis that DM reduces autoregulation effectiveness by reducing the spatial similarity of autoregulation. Male Long-Evans rats were divided into control (CON) and diabetic (DM; streptozotocin) groups and followed for either 1 wk (CON1, n = 6; DM1, n = 5) or 4 wk (CON4, n = 7; DM4, n = 7). At the end of the experiment, dynamic autoregulation was assessed in isoflurane-anesthetized rats by whole kidney RBF during baseline, NOS1 inhibition, and nonselective NOS inhibition. Kidney surface perfusion, monitored with laser speckle contrast imaging, was used to assess spatial heterogeneity of autoregulation. Autoregulation was significantly impaired in DM1 rats and not impaired in DM4 rats. l-NAME caused strong renal vasoconstriction in all rats, but did not significantly affect autoregulation dynamics. Autoregulation was more spatially heterogeneous in DM1, but not DM4. Therefore, our results, which are consistent with transient impairment of autoregulation in DM, argue against the hypothesis that this impairment is NO-dependent, and suggest that spatial properties of autoregulation may also contribute to reduced autoregulatory effectiveness in DM1.
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Affiliation(s)
- Nicholas Mitrou
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Sidney Morrison
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Paymon Mousavi
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Branko Braam
- Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada; and
- Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
| | - William A. Cupples
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
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Kokaze A, Ishikawa M, Matsunaga N, Karita K, Yoshida M, Ohtsu T, Ochiai H, Shirasawa T, Nanri H, Hoshino H, Takashima Y. Unexpected combined effects of NADH dehydrogenase subunit-2 237 Leu/Met polymorphism and green tea consumption on renal function in male Japanese health check-up examinees: a cross-sectional study. J Negat Results Biomed 2013; 12:17. [PMID: 24252463 PMCID: PMC3842666 DOI: 10.1186/1477-5751-12-17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 11/15/2013] [Indexed: 11/10/2022] Open
Abstract
Background NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in Japanese. A previous study has shown that ND2-237 Leu/Met polymorphism modulates the effects of green tea consumption on risk of hypertension. For men with ND2-237Leu, habitual green tea consumption may reduce the risk of hypertension. Moreover, there is a combined effect of ND2-237 Leu/Met polymorphism and alcohol consumption on risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2). Several beneficial effects of green tea on the kidney have been reported. The objective of this study was to investigate whether ND2-237 Leu/Met polymorphism modifies the effects of green tea consumption on risk of mildly decreased eGFR in male Japanese health check-up examinees. Results For ND2-237Leu genotypic men, after adjustment for confounding factors, green tea consumption may increase the risk of mildly decreased eGFR (P for trend = 0.016). The adjusted odds ratio (OR) for mildly decreased eGFR was significantly higher in subjects with ND2-237Leu who consume ≥6 cups of green tea per day than those who consume ≤1 cup of green tea per day (adjusted OR = 5.647, 95% confidence interval: 1.528-20.88, P = 0.009). On the other hand, for ND2-237Met genotypic men, green tea consumption does not appear to determine the risk of mildly decreased eGFR. Conclusion The present results suggest that ND2-237 Leu/Met polymorphism unexpectedly modifies the effects of green tea consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.
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Affiliation(s)
- Akatsuki Kokaze
- Department of Public Health, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
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Thompson CS. Diabetic nephropathy: Treatment with phosphodiesterase type 5 inhibitors. World J Diabetes 2013; 4:124-129. [PMID: 23961322 PMCID: PMC3746084 DOI: 10.4239/wjd.v4.i4.124] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 06/03/2013] [Accepted: 06/20/2013] [Indexed: 02/05/2023] Open
Abstract
The importance of nitric oxide (NO) in vascular physiology is irrefutable; it stimulates the intracellular production of cyclic guanosine monophosphate (cGMP), initiating vascular smooth muscle relaxation. This biochemical process increases the diameter of small arteries, regulating blood flow distribution between arterioles and the microvasculature. The kidney is no exception, since NO predominantly dilates the glomerular afferent arterioles. It is now evident that the vascular production of cGMP can be augmented by inhibitors of phosphodiesterase type 5 (PDE 5), the enzyme which breakdowns this cyclic nucleotide. This has clinical relevance, since diabetic nephropathy (DN) a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease, increases intraglomerular capillary pressure, leading to glomerular hypertension. PDE 5 inhibitors may have, therefore, the potential to reduce glomerular hypertension. This review describes the use of PDE 5 inhibitors to improve the metabolic, haemodynamic and inflammatory pathways/responses, all of which are dysfunctional in DN.
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Over-production of nitric oxide by oxidative stress-induced activation of the TGF-β1/PI3K/Akt pathway in mesangial cells cultured in high glucose. Acta Pharmacol Sin 2013; 34:507-14. [PMID: 23524565 DOI: 10.1038/aps.2012.207] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIM To investigate whether NO over-production in rat mesangial cells cultured in high glucose (HG) is related to activation of the TGF-β1/PI3K/Akt pathway. METHODS Rat mesangial cells line (HBZY-1) was exposed to HG (24.44 mmol/L) or H2O2 (10 μmol/L) for 16 h. NO release was quantified using the Griess assay. The TGF-β1 level was measured using ELISA. The protein expression of p-Akt, t-Akt, Bim, and iNOS was examined by Western blotting. The mRNA levels of TGF-β1 and Bim were measured using RT-PCR. The cell proliferation rate was estimated using a BrdU incorporation assay. RESULTS Treatment of the cells with HG, H2O2, or TGF-β1 (5 ng/mL) significantly increased the NO level that was substantially inhibited by co-treatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI), TGF-β1 inhibitor SB431542, or PI3K inhibitor LY294002. Both HG and H2O2 significantly increased the protein and mRNA levels of TGF-β1 in the cells, and HG-induced increases of TGF-β1 protein and mRNA were blocked by co-treatment with DPI. Furthermore, the treatment with HG or H2O2 significantly increased the expression of phosphorylated Akt and iNOS and cell proliferation rate, which was blocked by co-treatment with DPI, SB431542, or LY294002. Moreover, the treatment with HG or H2O2 significantly inhibited Bim protein and mRNA expression, which was reversed by co-treatment with DPI, SB431542, or LY294002. CONCLUSION The results demonstrate that high glucose causes oxidative stress and NO over-production in rat mesangial cells in vitro via decreasing Bim and increasing iNOS, which are at least partially mediated by the TGF-β1/PI3K/Akt pathway.
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Kokaze A, Ishikawa M, Matsunaga N, Karita K, Yoshida M, Shimada N, Ohtsu T, Shirasawa T, Ochiai H, Hoshino H, Takashima Y. Combined effect of mitochondrial DNA 5178 C/A polymorphism and alcohol consumption on estimated glomerular filtration rate in male Japanese health check-up examinees: a cross-sectional study. BMC Nephrol 2013; 14:35. [PMID: 23402433 PMCID: PMC3575228 DOI: 10.1186/1471-2369-14-35] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 02/04/2013] [Indexed: 12/05/2022] Open
Abstract
Background Prevention of chronic kidney disease (CKD) is a major public health issue. Although several studies have been performed on the association between alcohol consumption and CKD or renal function, it remains controversial. Numerous genetic polymorphisms have been reported to be associated with CKD and kidney function. Mitochondrial DNA cytosine/adenine (Mt5178 C/A) polymorphism is associated with longevity in Japanese. This polymorphism modifies the effects of alcohol consumption on blood pressure, risk of hypertension, serum triglyceride levels, risk of hyper-LDL cholesterolemia and serum uric acid levels. The objective of this study was to investigate whether Mt5178 C/A polymorphism modifies the effects of alcohol consumption on renal function in male Japanese health check-up examinees. Methods A total of 394 male subjects aged 29–76 years were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the combined effects of Mt5178 C/A polymorphism and habitual drinking on the risk of mildly decreased estimated glomerular filtration rate (eGFR) (<90 ml/min/1.73 m2) was conducted. Results For Mt5178A genotypic men, habitual drinking may increase eGFR (P for trend = 0.003) or reduce the risk of mildly decreased eGFR (P for trend = 0.003). Daily drinkers had a significantly higher eGFR than non-drinkers (P = 0.005). The crude odds ratio for decreased eGFR was significantly lower in daily drinkers than in non-drinkers (odds ratio = 0.092, 95% confidence interval: 0.012-0.727, P = 0.024). On the other hand, for Mt5178C genotypic men, habitual drinking does not appear to affect eGFR. Conclusion The present results suggest a joint effect of Mt5178 C/A polymorphism and alcohol consumption on eGFR and the risk of mildly decreased eGFR in male Japanese subjects.
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Affiliation(s)
- Akatsuki Kokaze
- Department of Public Health, Showa University School of Medicine, 1-5-8 Hatanodai, Tokyo 142-8555, Japan.
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Liao YC, Lee YH, Chuang LY, Guh JY, Shi MD, Huang JS. Advanced glycation end products-mediated hypertrophy is negatively regulated by tetrahydrobiopterin in renal tubular cells. Mol Cell Endocrinol 2012; 355:71-7. [PMID: 22326994 DOI: 10.1016/j.mce.2012.01.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Revised: 12/30/2011] [Accepted: 01/20/2012] [Indexed: 01/10/2023]
Abstract
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in DN. Elimination of tetrahydrobiopterin (BH(4)) and nitric oxide (NO) bioavailability may contribute to the aggravation of DN. The present study aims to explore any possible beneficial effect of exogenous BH(4) in alleviating the AGE-induced renal tubular hypertrophy in DN. Thus, renal tubular cells were treated with BH(4), BH(2), sepiapterin, or DAHP in the presence of AGE. We found that AGE (but not non-glycated BSA) markedly reduced NO production and increased hypertrophy index in these cells. Exogenous BH(4)/BH(2) and sepiapterin treatments attenuated AGE-inhibited the iNOS/NO/GTPCH I protein synthesis. Moreover, BH(4) and BH(2) significantly reversed AGE-enhanced the JAK2-STAT1/STAT3 activation. The abilities of BH(4) and BH(2) to inhibit AGE-induced renal cellular hypertrophy were verified by the observation that BH(4) and BH(2) inhibited hypertrophic growth and the protein synthesis of p27(Kip1) and α-SMA. These findings indicate for the first time that exogenous BH(4) and BH(2) attenuate AGE-induced hypertrophic effect at least partly by increasing the iNOS/GTPCH I synthesis and NO generation in renal tubular cells.
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Affiliation(s)
- Yi-Chen Liao
- Department of Dermatology, Chi Mei Medical Center, Tainan, Taiwan, ROC
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Khoshdel AR, Carney SL, Gillies A. Circulatory syndrome: an evolution of the metabolic syndrome concept! Curr Cardiol Rev 2012; 8:68-76. [PMID: 22845817 PMCID: PMC3394110 DOI: 10.2174/157340312801215773] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Revised: 03/28/2012] [Accepted: 04/03/2012] [Indexed: 02/08/2023] Open
Abstract
The metabolic syndrome has been a useful, though controversial construct in clinical practice as well as a valuable model in order to understand the interactions of diverse cardiovascular risk factors. However the increasing importance of the circulatory system in particular the endothelium, in both connecting and controlling organ function has underlined the limitations of the metabolic syndrome definition. The proposed "Circulatory Syndrome" is an attempt to refine the metabolic syndrome concept by the addition of recently documented markers of cardiovascular disease including renal impairment, microalbuminuria, arterial stiffness, ventricular dysfunction and anaemia to more classic factors including hypertension, dyslipidemia and abnormal glucose metabolism; all of which easily measured in clinical practice. These markers interact with each other as well as with other factors such as aging, obesity, physical inactivity, diet and smoking. The final common pathways of inflammation, oxidative stress and hypercoagulability thereby lead to endothelial damage and eventually cardiovascular disease. Nevertheless, the Circulatory (MARC) Syndrome, like its predecessor the metabolic syndrome, is only a small step toward an understanding of these complex and as yet poorly understood markers of disease.
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Affiliation(s)
- Ali Reza Khoshdel
- Department of Epidemiology, Faculty of Medicine, AJA University of medical Sciences, Tehran, Iran.
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Kuhad A, Sachdeva AK, Chopra K. Attenuation of renoinflammatory cascade in experimental model of diabetic nephropathy by sesamol. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2009; 57:6123-6128. [PMID: 19601660 DOI: 10.1021/jf901388g] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Diabetes has become the most common single cause of end-stage renal disease (ESRD) in the United States and Europe. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end ESRD. The study was designed to evaluate the impact of sesamol on renal function and renoinflammatory cascade in streptozotocin (STZ)-induced diabetes. STZ-induced diabetic rats were treated with sesamol (2, 4, and 8 mg/kg/day; po) or with vehicle from the fifth to eighth weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine, and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney were prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, nonprotein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1 beta (TGF-beta1), p65 subunit of NFkappabeta, and caspase-3. After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate, and active p65 subunit of NFkappabeta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of sesamol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Moreover, diabetic rats treated with insulin-sesamol combination produced more pronounced effect on molecular parameters as compared to their respective groups. The data reveal that sesamol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation, and apoptosis and thus exerts a marked renoprotective effect.
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Affiliation(s)
- Anurag Kuhad
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh 160 014, India
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Gumus II, Uz E, Bavbek N, Kargili A, Yanik B, Turgut FH, Akcay A, Turhan NO. Does glomerular hyperfiltration in pregnancy damage the kidney in women with more parities? Int Urol Nephrol 2009; 41:927-32. [PMID: 19575307 DOI: 10.1007/s11255-009-9586-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Accepted: 05/11/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVES We aimed to investigate the glomerular hyperfiltration due to pregnancy in women with more parities. METHODS Five hundred women aged 52.57 +/- 8.08 years, without a history of hypertension, diabetes mellitus or complicated pregnancy were involved in the study. They were divided into three groups. Group 1: women with no or one parity (n = 76); group 2: women with two or three parities (n = 333); group 3: women with four or more parities (n = 91). Laboratory parameters and demographical data were compared between the three groups. RESULTS Mean age, serum urea and serum creatinine were similar between three groups. Patients in group 3 had significantly higher GFR values compared to groups 1 and 2 (109.44 +/- 30.99, 110.76 +/- 30.22 and 121.92 +/- 34.73 mL/min/1.73 m(2) for groups 1, 2 and 3, respectively; P = 0.008 for group 1 vs group 3; P = 0.002 for group 2 vs group 3). CONCLUSIONS In our study, we suggest that glomerular hyperfiltration due to pregnancy does not have adverse effects on kidney in women with more parities. Pregnancy may have possible protective mechanisms for kidney against adverse effects of glomerular hyperfiltration.
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Affiliation(s)
- Ilknur Inegol Gumus
- Department of Obstetrics and Gynecology, Fatih University School of Medicine, Ankara, Turkey
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Huang JS, Chuang LY, Guh JY, Huang YJ. Effects of nitric oxide and antioxidants on advanced glycation end products-induced hypertrophic growth in human renal tubular cells. Toxicol Sci 2009; 111:109-19. [PMID: 19553346 DOI: 10.1093/toxsci/kfp134] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The accumulation of advanced glycation end products (AGE) is a key mediator of renal tubular hypertrophy in diabetic nephropathy (DN). Reactive oxygen species and nitric oxide (NO) were involved in the progression of DN. In this study, the molecular mechanisms of NO and antioxidants responsible for inhibition of AGE-induced renal tubular hypertrophy were examined. We found that AGE (but not nonglycated bovine serum albumin) significantly suppressed the NO/cGMP/PKG signaling in human renal proximal tubular cells. NO donors S-nitroso-N-acetylpenicillamine (SNAP)/sodium nitroprusside (SNP) and antioxidants N-acetylcysteine (NAC)/taurine treatments significantly attenuated AGE-inhibited NO production, cGMP synthesis, and inducible NO synthase/cGMP-dependent protein kinase (PKG) activation. Moreover, AGE-induced extracellular signal-regulated kinase/c-Jun N-terminal kinase/p38 mitogen-activated protein kinase activation was markedly blocked by antireceptor for AGE (RAGE), SNAP, SNP, NAC, and taurine. The abilities of NO and antioxidants to inhibit AGE/RAGE-induced hypertrophic growth were verified by the observation that SNAP, SNP, NAC, and taurine inhibited fibronectin, p21(Waf1/Cip1), and RAGE expression. Therefore, antioxidants significantly attenuated AGE/RAGE-enhanced cellular hypertrophy partly through induction of the NO/cGMP/PKG signaling.
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Affiliation(s)
- Jau-Shyang Huang
- Department of Biological Science and Technology, Chung Hwa University of Medical Technology, 717 Tainan.
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Kuhad A, Chopra K. Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci 2008; 84:296-301. [PMID: 19162042 DOI: 10.1016/j.lfs.2008.12.014] [Citation(s) in RCA: 157] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2008] [Revised: 12/04/2008] [Accepted: 12/12/2008] [Indexed: 12/16/2022]
Abstract
AIM Diabetic nephropathy is a serious complication for patients with diabetes mellitus. Approximately 30-40% of patients with type I and 15% with type II diabetes mellitus develop end stage renal disease. The study was designed to evaluate the impact of tocotrienol on renal function and reno-inflammatory cascade in streptozotocin-induced diabetes. MAIN METHODS Streptozotocin (STZ)-induced diabetic rats were treated with tocotrienol (25, 50 and 100 mg/kg), alpha-tocopherol (100 mg/kg) or with vehicle form 5th to 8th weeks. After 8 weeks, urine albumin excretion, urine output, serum creatinine, blood urea nitrogen, creatinine and urea clearance were measured. Cytoplasmic and nuclear fractions of kidney was prepared for the quantification of oxidative-nitrosative stress (lipid peroxidation, superoxide dismutase, catalase, non protein thiols, total nitric oxide), tumor necrosis factor-alpha (TNF-alpha), tissue growth factor-1beta (TGF-beta1), p65 subunit of NFkappabeta and caspase-3. KEY FINDINGS After 8 weeks of STZ injection, the rats produced significant alteration in renal function, increased oxidative-nitrosative stress, TNF-alpha, TGF-beta1, caspase-3 activity in cytoplasmic lysate and active p65 subunit of NFkappabeta in nuclear lysate of kidney of diabetic rats. Interestingly, co-administration of tocotrienol significantly and dose-dependently prevented biochemical and molecular changes associated with diabetes. Tocotrienol (100 mg/kg) was demonstrated to be more effective than alpha-tocopherol (100 mg/kg). Moreover, diabetic rats treated with insulin-tocotrienol combination produced more pronounced effect on molecular parameters as compared to their respective groups. SIGNIFICANCE Taken together, the data reveal that tocotrienol modulates the release of profibrotic cytokines, oxidative stress, ongoing chronic inflammation and apoptosis and thus exerts a marked renoprotective effect.
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Affiliation(s)
- Anurag Kuhad
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160 014, India
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Levine DZ, Iacovitti M, Robertson SJ. Modulation of single-nephron GFR in thedb/dbmouse model of type 2 diabetes mellitus. II. Effects of renal mass reduction. Am J Physiol Regul Integr Comp Physiol 2008; 294:R1840-6. [DOI: 10.1152/ajpregu.00457.2007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This study examines for the first time the effects of uninephrectomy (Nx) on modulation of whole kidney glomerular filtration rate (GFR), single-nephron GFR (SNGFR), and progression of diabetic nephropathy in the db/db mouse model of type 2 diabetes mellitus. To characterize SNGFR and tubuloglomerular feedback (TGF) responses to Nx and chronic neuronal nitric oxide synthase inhibition in the db/db mouse, we studied the effects of Nx on whole kidney GFR, SNGFR, and TGF characteristics in db/db and wild-type (WT) mice after Nx or sham Nx. We also documented progression of glomerular changes over a 6-mo period. Whole kidney GFR and SNGFR were significantly higher in db/db Nx than db/db sham mice, without change in proximal tubule reabsorptive rates. The TGF responses, determined as proximal-distal SNGFR differences, were brisk: 12.1 ± 1.0 vs. 8.4 ± 0.6 nl/min in WT sham ( P < 0.05), 15.7 ± 1.0 vs. 12.0 ± 1.0 nl/min in WT Nx ( P < 0.05), and 17.8 ± 1.3 vs. 14.3 ± 1.0 nl/min in db/db Nx ( P < 0.05) mice. Chronic ingestion of the neuronal nitric oxide synthase inhibitor S-methylthiocitrulline for 2–3 wk after Nx had no effect on SNGFR or the TGF response. These studies show further elevations in whole kidney GFR and SNGFR in these hyperglycemic morbidly obese db/db mice, with an intact TGF system after Nx. In addition, in the db/db Nx mice, 4–6 mo after Nx, there was an exacerbation of the lesions of diabetic nephropathy, as quantified by a significant increase in the ratio of mesangial surface area to total glomerular surface area.
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Navarro-González JF, Mora-Fernández C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19:433-42. [PMID: 18256353 DOI: 10.1681/asn.2007091048] [Citation(s) in RCA: 658] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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Affiliation(s)
- Juan F Navarro-González
- Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario, 145, 38010 Santa Cruz de Tenerife, Spain.
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Can rodent models of diabetic kidney disease clarify the significance of early hyperfiltration?: recognizing clinical and experimental uncertainties. Clin Sci (Lond) 2008; 114:109-18. [PMID: 18062776 DOI: 10.1042/cs20070088] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In the past, hyperfiltration and increased glomerular capillary pressure have been identified as important determinants of the development of DN (diabetic nephropathy). Recently, some basic research and clinical reviews on DN have omitted identifying hyperfiltration as an important risk factor. At the same time, different rodent models of DN have been described without and with documented hyperfiltration. In the present review, the importance of hyperfiltration is reassessed, reviewing key clinical and research studies, including the first single nephron studies in a mouse model of DN. From clinical studies of Type 1 and Type 2 diabetes mellitus, it is clear that many patients do not have early hyperfiltration and, even when present, its contribution to subsequent DN remains uncertain. Key mechanisms underlying hyperfiltration in rodent models are reviewed. Findings on intrarenal NO metabolism and the control of single-nephron GFR (glomerular filtration rate) in rodent models of DN are also presented. Characterization of valid experimental models of DN should include a careful delineation of the absence or presence of early hyperfiltration, with special efforts made to establish the specific role hyperfiltration may play in the emergence of DN.
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Pustovrh MC, Jawerbaum A, White V, Capobianco E, Higa R, Martínez N, López-Costa JJ, González E. The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats. Reproduction 2007; 134:605-13. [PMID: 17890296 DOI: 10.1530/rep-06-0267] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Matrix metalloproteinases (MMPs) play an important role in tissue remodeling that accompanies the rapid growth, differentiation, and structural changes of the placenta and several fetal organs. In the present study, we investigated whether the diabetic maternal environment may alter the regulatory homeostasis exerted by nitric oxide (NO) on MMPs activity in the feto-placental unit from rats at midgestation. We found that NADPH-diaphorase activity, which reflects the distribution and activity of NO synthases (NOS), was increased in both placenta and fetuses from diabetic rats when compared with controls. In addition, while a NO donor enhanced MMP2 and MMP9 activities, a NOS inhibitor reduced these activities in the maternal side of the placenta from control rats. This regulatory effect of NO was only observed on MMP9 in the diabetic group. On the other hand, the NO donor did not modify MMP2 and MMP9 activities, while the NOS inhibitor reduced MMP9 activity in the fetal side of both control and diabetic placentas. In the fetuses, MMP2 was enhanced by the NO donor and reduced by the NO inhibitor in both fetuses from control and diabetic rats. Overall, this study demonstrates that NO is able to modulate the activation of MMPs in the feto-placental unit, and provides supportive evidence that increased NOS activity leads to NO overproduction in the feto-placental unit from diabetic rats, an alteration closely related to the observed MMPs dysregulation that may have profound implications in the formation and function of the placenta and the fetal organs.
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Affiliation(s)
- M C Pustovrh
- Laboratory of Reproduction and Metabolism, Center for Pharmacological and Botanical Studies, CEFyBO-CONICET, University of Buenos Aires, Paraguay, Buenos Aires, Argentina
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