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Mechanisms by which heme oxygenase rescue renal dysfunction in obesity

Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme-oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal pro...

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Autores principales: Ndisang, Joseph Fomusi, Tiwari, Shuchita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215395/
https://www.ncbi.nlm.nih.gov/pubmed/25460740
http://dx.doi.org/10.1016/j.redox.2014.09.001
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author Ndisang, Joseph Fomusi
Tiwari, Shuchita
author_facet Ndisang, Joseph Fomusi
Tiwari, Shuchita
author_sort Ndisang, Joseph Fomusi
collection PubMed
description Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme-oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal proteins like podocin, podocalyxin, CD2-associated-protein (CD2AP) and proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2 in renal tissue from normoglycemic obese Zucker-fatty rats (ZFs) have not been reported. Treatment with hemin reduced renal histo-pathological lesions including glomerular-hypertrophy, tubular-cast, tubular-atrophy and mononuclear cell-infiltration in ZFs. These were associated with enhanced expression of beta-catenin, Oct3/4, WT1, Pax2 and nephrin, an essential transmembrane protein required for the formation of the scaffoldings of the podocyte slit-diaphragm, permitting the filtration of small ions, but not massive excretion of proteins, hence proteinuria. Besides nephrin, hemin also enhanced other important podocyte-regulators including, podocalyxin, podocin and CD2AP. Correspondingly, important markers of renal dysfunction such as albuminuria and proteinuria were reduced, while creatinine clearance increased, suggesting improved renal function in hemin-treated ZFs. The renoprotection by hemin was accompanied by the reduction of inflammatory/oxidative mediators including, macrophage-inflammatory-protein-1α, macrophage-chemoattractant-protein-1 and 8-isoprostane, whereas HO-1, HO-activity and the total-anti-oxidant-capacity increased. Contrarily, the HO-inhibitor, stannous-mesoporphyrin nullified the reno-protection by hemin. Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity.
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spelling pubmed-42153952014-11-06 Mechanisms by which heme oxygenase rescue renal dysfunction in obesity Ndisang, Joseph Fomusi Tiwari, Shuchita Redox Biol Research Paper Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme-oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal proteins like podocin, podocalyxin, CD2-associated-protein (CD2AP) and proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2 in renal tissue from normoglycemic obese Zucker-fatty rats (ZFs) have not been reported. Treatment with hemin reduced renal histo-pathological lesions including glomerular-hypertrophy, tubular-cast, tubular-atrophy and mononuclear cell-infiltration in ZFs. These were associated with enhanced expression of beta-catenin, Oct3/4, WT1, Pax2 and nephrin, an essential transmembrane protein required for the formation of the scaffoldings of the podocyte slit-diaphragm, permitting the filtration of small ions, but not massive excretion of proteins, hence proteinuria. Besides nephrin, hemin also enhanced other important podocyte-regulators including, podocalyxin, podocin and CD2AP. Correspondingly, important markers of renal dysfunction such as albuminuria and proteinuria were reduced, while creatinine clearance increased, suggesting improved renal function in hemin-treated ZFs. The renoprotection by hemin was accompanied by the reduction of inflammatory/oxidative mediators including, macrophage-inflammatory-protein-1α, macrophage-chemoattractant-protein-1 and 8-isoprostane, whereas HO-1, HO-activity and the total-anti-oxidant-capacity increased. Contrarily, the HO-inhibitor, stannous-mesoporphyrin nullified the reno-protection by hemin. Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity. Elsevier 2014-09-06 /pmc/articles/PMC4215395/ /pubmed/25460740 http://dx.doi.org/10.1016/j.redox.2014.09.001 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Research Paper
Ndisang, Joseph Fomusi
Tiwari, Shuchita
Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title_full Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title_fullStr Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title_full_unstemmed Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title_short Mechanisms by which heme oxygenase rescue renal dysfunction in obesity
title_sort mechanisms by which heme oxygenase rescue renal dysfunction in obesity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215395/
https://www.ncbi.nlm.nih.gov/pubmed/25460740
http://dx.doi.org/10.1016/j.redox.2014.09.001
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