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SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor β1.

Mortuza R, Feng B, Chakrabarti S - J. Cell. Mol. Med. (2015)

Bottom Line: Previously we showed glucose reduces sirtuin1 (SIRT1), a class III histone deacetylase.These cells also showed increased p300 expression, histone acetylation and reduced SIRT1 levels.These changes were rectified in the ECs following p300 silencing or by SIRT1 overexpression, whereas SIRT1 knockdown or p300 overexpression in NG mimicked the effects of HG.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.

No MeSH data available.


Related in: MedlinePlus

SIRT1 overexpressing diabetic mice shows reduced p300 expressions in the kidney and retina. Transgenic mice with SIRT1 overexpression (SIRT1 Tg) showed increased expressions of (A and B) SIRT1 mRNA levels and (C and D) enzyme activity in the kidneys and retinas of diabetic and control animals. Such overexpression averted diabetes-induced increased (E and F) p300 mRNA levels and (G) histone acetylation (Ac-H3K9/14) in these tissues. Control = Non-diabetic wild-type, Co+SIRT1 Tg = SIRT1 transgenic mice non-diabetic, Diabetic = Wild-type diabetic, Di+SIRT1 Tg = SIRT1 transgenic mice diabetic, Co = Control, Di =Diabetic, * = significantly different from control, ╪ = significantly different from Diabetic. mRNA levels are expressed as a ratio of 18s. All data (mean ± SEM, P < 0.05) were normalized to Co; n = 8–10/group).
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fig04: SIRT1 overexpressing diabetic mice shows reduced p300 expressions in the kidney and retina. Transgenic mice with SIRT1 overexpression (SIRT1 Tg) showed increased expressions of (A and B) SIRT1 mRNA levels and (C and D) enzyme activity in the kidneys and retinas of diabetic and control animals. Such overexpression averted diabetes-induced increased (E and F) p300 mRNA levels and (G) histone acetylation (Ac-H3K9/14) in these tissues. Control = Non-diabetic wild-type, Co+SIRT1 Tg = SIRT1 transgenic mice non-diabetic, Diabetic = Wild-type diabetic, Di+SIRT1 Tg = SIRT1 transgenic mice diabetic, Co = Control, Di =Diabetic, * = significantly different from control, ╪ = significantly different from Diabetic. mRNA levels are expressed as a ratio of 18s. All data (mean ± SEM, P < 0.05) were normalized to Co; n = 8–10/group).

Mentions: Following the establishment that SIRT1 regulated ET-1 and TGF-β1 in ECs, we expanded our study to investigate whether the mechanisms seen in these cells was important in the development of renal and retinal microangiopathy in a well-established animal model. Streptozotocin-induced diabetic mice showed hyperglycaemia (diabetics 21.91 ± 4.58 mmol/l versus controls 7.38 ± 0.91 mmol/l, P < 0.001) and reduced bodyweight (diabetics 22.80 ± 1.40 g versus controls 30.25 ± 2.36 g, P < 0.001). Initially we performed real time RT-PCR analysis of the renal and retinal tissue from these mice following 2 months of uncontrolled diabetes. We have previously shown that diabetes induced increased ECM protein and vasoactive factor expression is established at this time-point 19,20,24–27. mRNA analysis showed that diabetic mice had significant down-regulation of SIRT1 expressions in the kidneys and retinas (Fig.4A and B). This finding was further reflected in the SIRT1 enzyme activity levels (Fig.4C and D). Moreover, these mice showed significant up-regulation of p300 mRNA levels in the renal and retinal tissues which were abrogated in SIRT1 overexpressing diabetic mice (Fig.4E and F). Western blot analysis further showed that SIRT1 overexpression caused reduction in histone acetylation (Ac-H3K9/14) in these tissues demonstrating the downstream functional consequences of p300 alteration in these tissues (Fig.4G). Absence of Rd8 mutation 28 in the transgenic mice were confirmed with genotyping (Fig. S2A). Microscopic examination of renal and retinal tissues showed no morphologically evident lesions (Fig. S2B).


SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor β1.

Mortuza R, Feng B, Chakrabarti S - J. Cell. Mol. Med. (2015)

SIRT1 overexpressing diabetic mice shows reduced p300 expressions in the kidney and retina. Transgenic mice with SIRT1 overexpression (SIRT1 Tg) showed increased expressions of (A and B) SIRT1 mRNA levels and (C and D) enzyme activity in the kidneys and retinas of diabetic and control animals. Such overexpression averted diabetes-induced increased (E and F) p300 mRNA levels and (G) histone acetylation (Ac-H3K9/14) in these tissues. Control = Non-diabetic wild-type, Co+SIRT1 Tg = SIRT1 transgenic mice non-diabetic, Diabetic = Wild-type diabetic, Di+SIRT1 Tg = SIRT1 transgenic mice diabetic, Co = Control, Di =Diabetic, * = significantly different from control, ╪ = significantly different from Diabetic. mRNA levels are expressed as a ratio of 18s. All data (mean ± SEM, P < 0.05) were normalized to Co; n = 8–10/group).
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Related In: Results  -  Collection

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fig04: SIRT1 overexpressing diabetic mice shows reduced p300 expressions in the kidney and retina. Transgenic mice with SIRT1 overexpression (SIRT1 Tg) showed increased expressions of (A and B) SIRT1 mRNA levels and (C and D) enzyme activity in the kidneys and retinas of diabetic and control animals. Such overexpression averted diabetes-induced increased (E and F) p300 mRNA levels and (G) histone acetylation (Ac-H3K9/14) in these tissues. Control = Non-diabetic wild-type, Co+SIRT1 Tg = SIRT1 transgenic mice non-diabetic, Diabetic = Wild-type diabetic, Di+SIRT1 Tg = SIRT1 transgenic mice diabetic, Co = Control, Di =Diabetic, * = significantly different from control, ╪ = significantly different from Diabetic. mRNA levels are expressed as a ratio of 18s. All data (mean ± SEM, P < 0.05) were normalized to Co; n = 8–10/group).
Mentions: Following the establishment that SIRT1 regulated ET-1 and TGF-β1 in ECs, we expanded our study to investigate whether the mechanisms seen in these cells was important in the development of renal and retinal microangiopathy in a well-established animal model. Streptozotocin-induced diabetic mice showed hyperglycaemia (diabetics 21.91 ± 4.58 mmol/l versus controls 7.38 ± 0.91 mmol/l, P < 0.001) and reduced bodyweight (diabetics 22.80 ± 1.40 g versus controls 30.25 ± 2.36 g, P < 0.001). Initially we performed real time RT-PCR analysis of the renal and retinal tissue from these mice following 2 months of uncontrolled diabetes. We have previously shown that diabetes induced increased ECM protein and vasoactive factor expression is established at this time-point 19,20,24–27. mRNA analysis showed that diabetic mice had significant down-regulation of SIRT1 expressions in the kidneys and retinas (Fig.4A and B). This finding was further reflected in the SIRT1 enzyme activity levels (Fig.4C and D). Moreover, these mice showed significant up-regulation of p300 mRNA levels in the renal and retinal tissues which were abrogated in SIRT1 overexpressing diabetic mice (Fig.4E and F). Western blot analysis further showed that SIRT1 overexpression caused reduction in histone acetylation (Ac-H3K9/14) in these tissues demonstrating the downstream functional consequences of p300 alteration in these tissues (Fig.4G). Absence of Rd8 mutation 28 in the transgenic mice were confirmed with genotyping (Fig. S2A). Microscopic examination of renal and retinal tissues showed no morphologically evident lesions (Fig. S2B).

Bottom Line: Previously we showed glucose reduces sirtuin1 (SIRT1), a class III histone deacetylase.These cells also showed increased p300 expression, histone acetylation and reduced SIRT1 levels.These changes were rectified in the ECs following p300 silencing or by SIRT1 overexpression, whereas SIRT1 knockdown or p300 overexpression in NG mimicked the effects of HG.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.

No MeSH data available.


Related in: MedlinePlus