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Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats

Efekti hronične primene losartana i tempola u eksperimentalnom modelu fokalno segmentne glomeruloskleroze kod spontano hipertenzivnih pacova

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2018
1113.pdf (5.917Mb)
Authors
Karanović, Danijela
Contributors
Grujić Milanović, Jelica
Đorđević, Jelena
Mihailović-Stanojević, Nevena
Doctoral thesis (Published version)
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Abstract
Previous studies have shown that renin angiotensin system (RAS) plays an important role in the pathogenesis and progression of focal segmental glomerulosclerosis (FSGS). Oxidative stress is involved in the development and progression of chronic kidney disease. However, the association of oxidative stress and RAS in the progression of FSGS has not been completely elucidated. In this study we investigated the effects of chronic tempol (free radical scavenger, SOD mimetic), losartan (selective angiotensin II type 1 receptor (AT1R) blocker), and their combined treatment in slowing down the progression of FSGS, in spontaneously hypertensive (SH) rats with adriamycin (ADR) nephropathy. Animals were initially divided into two experimental groups: control (SHC) and group that received ADR 2 mg/kg i.v. twice in an interval of 21 days. After the second injection of ADR, the animals were given tap water (SHADR), losartan (SHADR+L), tempol (SHADR+T) or combined treatment (SHADR+T+L) by gavage. Hem...odynamic measurements were performed, blood, urine, and kidney samples were taken for biochemical and histopathological analysis. Immunohistochemical method was used for protein expression and localization of the nestin and vimentin, proteins of cytoskeleton network, and change in their protein expression is a marker of cell injury. Matrix metalloproteinase-1 (MMP-1), which participates in the degradation of the extracellular matrix components and preserving the integrity of the glomerulus, was determined by the ELISA method. The parameters of oxidative stress: lipid peroxidation, protein carbonyl content (PCOs); antioxidant defense: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and antioxidant capacity were analysed. Immunohistochemical, Western blot and ELISA method were used for analysis of the Nox2 and Nox4 protein expression, isoforms of the catalytic subunit of NADPH oxidase, the main source of reactive oxygen species in the cell, involved in the inflammation process. Protein expression of three isoforms of azote monoxide synthase, inducible (iNOS), endothelial (eNOS), and neuronal (nNOS) were determined by Western blot and immunohistochemical method in the kidney. Total metabolites of NO (nitrites, nitrates) were measured in the kidney and urine...

Dosadašnja istraživanja pokazala su da renin angiotenzin sistem (RAS) ima važnu ulogu u patogenezi i progresiji fokalno segmentne glomeruloskleroze (FSGS). Oksidativni stres je prisutan u hroničnoj bubrežnoj slabosti i doprinosi progresiji bolesti. Povezanost oksidativnog stresa i RAS u procesima progresije FSGS još je nedovoljno razjašnjena. Stoga su istraživanja u okviru ove disertacije bila usmerena ka ispitivanju efekata hronične primene tempola (sakupljač slobodnih radikala, SOD mimetik), losartana (blokator receptora za angiotenzin II tipa 1, AT1R), kao i njihove kombinacije, na usporavanje progresije FSGS izazvane adrijamicinom (ADR) kod spontano hipertenzivnih (SH) pacova. Životinje su inicijalno deljene u dve eksperimentalne grupe, kontrolnu (SHC) i grupu koja je primila ADR 2 mg/kg i.v. dva puta u intervalu od 21 dan. Nakon druge injekcije ADR, životinje su dobijale vodu (SHADR), losartan (SHADR+L), tempol (SHADR+T) i kombinovani tretman (SHADR+T+L) gavažom. Na kraju šeste ne...delje tretmana vršena su hemodinamska merenja i uzorkovanje krvi, urina i bubrega. Na osnovu biohemijskih parametara vršena je procena lipidnog statusa i bubrežne funkcije. Urađena je histopatološka analiza bubrega. Imunihistohemijskom metodom ispitivani su proteini citosketeta, nestin i vimentin, čije izmenjene ekspresije su pokazatelj oštećenja bubrežnog tkiva. Matriksna metaloproteinaza-1 (MMP-1), koja učestvuje u degradaciji komponenti vanćelijskog mariksa i očuvanju integriteta glomerula, određivana je ELISA metodom. Ispitivani su parametri oksidativnog stresa: lipidna peroksidacija i nivo karbonilovanih proteina (PCOs); aktivnosti enzima antioksidativnog sistema: superoksid dismutaze (SOD), katalaze (CAT), glutation peroksidaze (GPx) i glutation reduktaze (GR); kao i antioksidativni kapacitet. Primenom imunohistohemijske, Western blot i ELISA metode u bubrezima su određivane ekspresije Nox2 i Nox4 izoforme katalitičke subjedinice NADPH oksidaze, glavni izvor reaktivnih kiseoničnih vrsta u ćeliji, uključene u proces inflamacije. Ekspresija proteina tri izoforme azot-monoksid sintaze, inducibilna (iNOS), endotelna (eNOS) i neuronska (nNOS), određivane su Western blot i imunohistohemijskom metodom u tkivu bubrega. Određivani su ukupni metaboliti NO-a (nitriti, nitrati) u urinu i bubrezima...

Keywords:
focal segmental glomerulosclerosis / adriamycin nephropathy / spontaneously hypertensive rats / angiotensin II type 1 receptor / tempol / oxidative stress / nitric oxide synthase / fokalno segmentna glomeruloskleroza / adrijamicinska nefropatija / spontano hipertenzivni pacovi / blokator receptora za angiotenzin II tipa 1 / tempol / oksidativni stres / azot-monoksid sintaza
Source:
2018
Publisher:
  • Univerzitet u Beogradu, Biološki fakultet
Funding / projects:
  • Investigation of antihypertensiv? and renoprotectiv? potential of natural and synthetic compounds in the experimental models of cardiovascular and renal diseases (RS-175096)
[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_nardus_10119
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=6135
http://nardus.mpn.gov.rs/handle/123456789/10119
https://fedorabg.bg.ac.rs/fedora/get/o:18601/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025205426
http://rimi.imi.bg.ac.rs/handle/123456789/1116
Collections
  • Doktorati / Doctoral thesis
Institution/Community
Institut za medicinska istraživanja
TY  - THES
AU  - Karanović, Danijela
PY  - 2018
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=6135
UR  - http://nardus.mpn.gov.rs/handle/123456789/10119
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:18601/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025205426
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1116
AB  - Previous studies have shown that renin angiotensin system (RAS) plays an important role in the pathogenesis and progression of focal segmental glomerulosclerosis (FSGS). Oxidative stress is involved in the development and progression of chronic kidney disease. However, the association of oxidative stress and RAS in the progression of FSGS has not been completely elucidated. In this study we investigated the effects of chronic tempol (free radical scavenger, SOD mimetic), losartan (selective angiotensin II type 1 receptor (AT1R) blocker), and their combined treatment in slowing down the progression of FSGS, in spontaneously hypertensive (SH) rats with adriamycin (ADR) nephropathy. Animals were initially divided into two experimental groups: control (SHC) and group that received ADR 2 mg/kg i.v. twice in an interval of 21 days. After the second injection of ADR, the animals were given tap water (SHADR), losartan (SHADR+L), tempol (SHADR+T) or combined treatment (SHADR+T+L) by gavage. Hemodynamic measurements were performed, blood, urine, and kidney samples were taken for biochemical and histopathological analysis. Immunohistochemical method was used for protein expression and localization of the nestin and vimentin, proteins of cytoskeleton network, and change in their protein expression is a marker of cell injury. Matrix metalloproteinase-1 (MMP-1), which participates in the degradation of the extracellular matrix components and preserving the integrity of the glomerulus, was determined by the ELISA method. The parameters of oxidative stress: lipid peroxidation, protein carbonyl content (PCOs); antioxidant defense: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and antioxidant capacity were analysed. Immunohistochemical, Western blot and ELISA method were used for analysis of the Nox2 and Nox4 protein expression, isoforms of the catalytic subunit of NADPH oxidase, the main source of reactive oxygen species in the cell, involved in the inflammation process. Protein expression of three isoforms of azote monoxide synthase, inducible (iNOS), endothelial (eNOS), and neuronal (nNOS) were determined by Western blot and immunohistochemical method in the kidney. Total metabolites of NO (nitrites, nitrates) were measured in the kidney and urine...
AB  - Dosadašnja istraživanja pokazala su da renin angiotenzin sistem (RAS) ima važnu ulogu u patogenezi i progresiji fokalno segmentne glomeruloskleroze (FSGS). Oksidativni stres je prisutan u hroničnoj bubrežnoj slabosti i doprinosi progresiji bolesti. Povezanost oksidativnog stresa i RAS u procesima progresije FSGS još je nedovoljno razjašnjena. Stoga su istraživanja u okviru ove disertacije bila usmerena ka ispitivanju efekata hronične primene tempola (sakupljač slobodnih radikala, SOD mimetik), losartana (blokator receptora za angiotenzin II tipa 1, AT1R), kao i njihove kombinacije, na usporavanje progresije FSGS izazvane adrijamicinom (ADR) kod spontano hipertenzivnih (SH) pacova. Životinje su inicijalno deljene u dve eksperimentalne grupe, kontrolnu (SHC) i grupu koja je primila ADR 2 mg/kg i.v. dva puta u intervalu od 21 dan. Nakon druge injekcije ADR, životinje su dobijale vodu (SHADR), losartan (SHADR+L), tempol (SHADR+T) i kombinovani tretman (SHADR+T+L) gavažom. Na kraju šeste nedelje tretmana vršena su hemodinamska merenja i uzorkovanje krvi, urina i bubrega. Na osnovu biohemijskih parametara vršena je procena lipidnog statusa i bubrežne funkcije. Urađena je histopatološka analiza bubrega. Imunihistohemijskom metodom ispitivani su proteini citosketeta, nestin i vimentin, čije izmenjene ekspresije su pokazatelj oštećenja bubrežnog tkiva. Matriksna metaloproteinaza-1 (MMP-1), koja učestvuje u degradaciji komponenti vanćelijskog mariksa i očuvanju integriteta glomerula, određivana je ELISA metodom. Ispitivani su parametri oksidativnog stresa: lipidna peroksidacija i nivo karbonilovanih proteina (PCOs); aktivnosti enzima antioksidativnog sistema: superoksid dismutaze (SOD), katalaze (CAT), glutation peroksidaze (GPx) i glutation reduktaze (GR); kao i antioksidativni kapacitet. Primenom imunohistohemijske, Western blot i ELISA metode u bubrezima su određivane ekspresije Nox2 i Nox4 izoforme katalitičke subjedinice NADPH oksidaze, glavni izvor reaktivnih kiseoničnih vrsta u ćeliji, uključene u proces inflamacije. Ekspresija proteina tri izoforme azot-monoksid sintaze, inducibilna (iNOS), endotelna (eNOS) i neuronska (nNOS), određivane su Western blot i imunohistohemijskom metodom u tkivu bubrega. Određivani su ukupni metaboliti NO-a (nitriti, nitrati) u urinu i bubrezima...
PB  - Univerzitet u Beogradu, Biološki fakultet
T1  - Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats
T1  - Efekti hronične primene losartana i tempola u eksperimentalnom modelu fokalno segmentne glomeruloskleroze kod spontano hipertenzivnih pacova
UR  - t-223
UR  - https://hdl.handle.net/21.15107/rcub_nardus_10119
ER  - 
@phdthesis{
author = "Karanović, Danijela",
year = "2018",
abstract = "Previous studies have shown that renin angiotensin system (RAS) plays an important role in the pathogenesis and progression of focal segmental glomerulosclerosis (FSGS). Oxidative stress is involved in the development and progression of chronic kidney disease. However, the association of oxidative stress and RAS in the progression of FSGS has not been completely elucidated. In this study we investigated the effects of chronic tempol (free radical scavenger, SOD mimetic), losartan (selective angiotensin II type 1 receptor (AT1R) blocker), and their combined treatment in slowing down the progression of FSGS, in spontaneously hypertensive (SH) rats with adriamycin (ADR) nephropathy. Animals were initially divided into two experimental groups: control (SHC) and group that received ADR 2 mg/kg i.v. twice in an interval of 21 days. After the second injection of ADR, the animals were given tap water (SHADR), losartan (SHADR+L), tempol (SHADR+T) or combined treatment (SHADR+T+L) by gavage. Hemodynamic measurements were performed, blood, urine, and kidney samples were taken for biochemical and histopathological analysis. Immunohistochemical method was used for protein expression and localization of the nestin and vimentin, proteins of cytoskeleton network, and change in their protein expression is a marker of cell injury. Matrix metalloproteinase-1 (MMP-1), which participates in the degradation of the extracellular matrix components and preserving the integrity of the glomerulus, was determined by the ELISA method. The parameters of oxidative stress: lipid peroxidation, protein carbonyl content (PCOs); antioxidant defense: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and antioxidant capacity were analysed. Immunohistochemical, Western blot and ELISA method were used for analysis of the Nox2 and Nox4 protein expression, isoforms of the catalytic subunit of NADPH oxidase, the main source of reactive oxygen species in the cell, involved in the inflammation process. Protein expression of three isoforms of azote monoxide synthase, inducible (iNOS), endothelial (eNOS), and neuronal (nNOS) were determined by Western blot and immunohistochemical method in the kidney. Total metabolites of NO (nitrites, nitrates) were measured in the kidney and urine..., Dosadašnja istraživanja pokazala su da renin angiotenzin sistem (RAS) ima važnu ulogu u patogenezi i progresiji fokalno segmentne glomeruloskleroze (FSGS). Oksidativni stres je prisutan u hroničnoj bubrežnoj slabosti i doprinosi progresiji bolesti. Povezanost oksidativnog stresa i RAS u procesima progresije FSGS još je nedovoljno razjašnjena. Stoga su istraživanja u okviru ove disertacije bila usmerena ka ispitivanju efekata hronične primene tempola (sakupljač slobodnih radikala, SOD mimetik), losartana (blokator receptora za angiotenzin II tipa 1, AT1R), kao i njihove kombinacije, na usporavanje progresije FSGS izazvane adrijamicinom (ADR) kod spontano hipertenzivnih (SH) pacova. Životinje su inicijalno deljene u dve eksperimentalne grupe, kontrolnu (SHC) i grupu koja je primila ADR 2 mg/kg i.v. dva puta u intervalu od 21 dan. Nakon druge injekcije ADR, životinje su dobijale vodu (SHADR), losartan (SHADR+L), tempol (SHADR+T) i kombinovani tretman (SHADR+T+L) gavažom. Na kraju šeste nedelje tretmana vršena su hemodinamska merenja i uzorkovanje krvi, urina i bubrega. Na osnovu biohemijskih parametara vršena je procena lipidnog statusa i bubrežne funkcije. Urađena je histopatološka analiza bubrega. Imunihistohemijskom metodom ispitivani su proteini citosketeta, nestin i vimentin, čije izmenjene ekspresije su pokazatelj oštećenja bubrežnog tkiva. Matriksna metaloproteinaza-1 (MMP-1), koja učestvuje u degradaciji komponenti vanćelijskog mariksa i očuvanju integriteta glomerula, određivana je ELISA metodom. Ispitivani su parametri oksidativnog stresa: lipidna peroksidacija i nivo karbonilovanih proteina (PCOs); aktivnosti enzima antioksidativnog sistema: superoksid dismutaze (SOD), katalaze (CAT), glutation peroksidaze (GPx) i glutation reduktaze (GR); kao i antioksidativni kapacitet. Primenom imunohistohemijske, Western blot i ELISA metode u bubrezima su određivane ekspresije Nox2 i Nox4 izoforme katalitičke subjedinice NADPH oksidaze, glavni izvor reaktivnih kiseoničnih vrsta u ćeliji, uključene u proces inflamacije. Ekspresija proteina tri izoforme azot-monoksid sintaze, inducibilna (iNOS), endotelna (eNOS) i neuronska (nNOS), određivane su Western blot i imunohistohemijskom metodom u tkivu bubrega. Određivani su ukupni metaboliti NO-a (nitriti, nitrati) u urinu i bubrezima...",
publisher = "Univerzitet u Beogradu, Biološki fakultet",
title = "Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats, Efekti hronične primene losartana i tempola u eksperimentalnom modelu fokalno segmentne glomeruloskleroze kod spontano hipertenzivnih pacova",
url = "t-223, https://hdl.handle.net/21.15107/rcub_nardus_10119"
}
Karanović, D.. (2018). Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats. 
Univerzitet u Beogradu, Biološki fakultet..
t-223
Karanović D. Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats. 2018;.
t-223 .
Karanović, Danijela, "Effects of chronic losartan and tempol treatments on experimental focal segmental glomerulosclerosis in spontaneously hypertensive rats" (2018),
t-223 .

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