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Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Bottom Line: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects.Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy.Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.

Research design and methods: To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.

Results: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

Conclusions: Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

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Related in: MedlinePlus

Treg depletion fosters organ damage in diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intraperitoneally received an anti-CD25 antibody on the day of and 4 weeks after uninephrectomy (white bar, n = 8). Control animals received an isotype control antibody (black bar, n = 8). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B: After 56 days, kidneys were harvested and the glomerular diameter was measured. Kidney sections were stained for the infiltration of CD4+ and CD8+ T cells (C) as well as F4/80+ cells and CD68+ macrophages (D). Hpf, high-power field. E: The cytokine response in the kidney was evaluated by real-time PCR. The fold increase to the mean expression of control animals is provided. Pooled data of two independent experiments are shown. *P < 0.05.
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Figure 4: Treg depletion fosters organ damage in diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intraperitoneally received an anti-CD25 antibody on the day of and 4 weeks after uninephrectomy (white bar, n = 8). Control animals received an isotype control antibody (black bar, n = 8). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B: After 56 days, kidneys were harvested and the glomerular diameter was measured. Kidney sections were stained for the infiltration of CD4+ and CD8+ T cells (C) as well as F4/80+ cells and CD68+ macrophages (D). Hpf, high-power field. E: The cytokine response in the kidney was evaluated by real-time PCR. The fold increase to the mean expression of control animals is provided. Pooled data of two independent experiments are shown. *P < 0.05.

Mentions: The urinary albumin-to-creatinine ratio as a marker of renal impairment was increased in Treg-depleted versus nondepleted db/db mice starting on day 28 and reached statistical significance on day 42 after uninephrectomy (Fig. 4A). Accordingly, the glomerular diameter was found to be significantly increased in Treg-depleted mice on day 56 after uninephrectomy (Fig. 4B). Semiquantitative assessment of renal inflammatory cell infiltration revealed a profound increase in CD4+ and CD8+ T cells in the kidneys of Treg-depleted db/db mice (Fig. 4C), whereas F4/80+ cells and CD68-expressing macrophages were not different (Fig. 4D). Real-time analysis revealed a significantly increased mRNA expression of the Th1 cytokine TNF-α in the kidneys of Treg-depleted db/db mice (Fig. 4E). IFN-γ and IL-10 tended to be increased in Treg-depleted mice, whereas IL-6 and Gata-3 were not differentially regulated (Fig. 4E).


Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Treg depletion fosters organ damage in diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intraperitoneally received an anti-CD25 antibody on the day of and 4 weeks after uninephrectomy (white bar, n = 8). Control animals received an isotype control antibody (black bar, n = 8). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B: After 56 days, kidneys were harvested and the glomerular diameter was measured. Kidney sections were stained for the infiltration of CD4+ and CD8+ T cells (C) as well as F4/80+ cells and CD68+ macrophages (D). Hpf, high-power field. E: The cytokine response in the kidney was evaluated by real-time PCR. The fold increase to the mean expression of control animals is provided. Pooled data of two independent experiments are shown. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198056&req=5

Figure 4: Treg depletion fosters organ damage in diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intraperitoneally received an anti-CD25 antibody on the day of and 4 weeks after uninephrectomy (white bar, n = 8). Control animals received an isotype control antibody (black bar, n = 8). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B: After 56 days, kidneys were harvested and the glomerular diameter was measured. Kidney sections were stained for the infiltration of CD4+ and CD8+ T cells (C) as well as F4/80+ cells and CD68+ macrophages (D). Hpf, high-power field. E: The cytokine response in the kidney was evaluated by real-time PCR. The fold increase to the mean expression of control animals is provided. Pooled data of two independent experiments are shown. *P < 0.05.
Mentions: The urinary albumin-to-creatinine ratio as a marker of renal impairment was increased in Treg-depleted versus nondepleted db/db mice starting on day 28 and reached statistical significance on day 42 after uninephrectomy (Fig. 4A). Accordingly, the glomerular diameter was found to be significantly increased in Treg-depleted mice on day 56 after uninephrectomy (Fig. 4B). Semiquantitative assessment of renal inflammatory cell infiltration revealed a profound increase in CD4+ and CD8+ T cells in the kidneys of Treg-depleted db/db mice (Fig. 4C), whereas F4/80+ cells and CD68-expressing macrophages were not different (Fig. 4D). Real-time analysis revealed a significantly increased mRNA expression of the Th1 cytokine TNF-α in the kidneys of Treg-depleted db/db mice (Fig. 4E). IFN-γ and IL-10 tended to be increased in Treg-depleted mice, whereas IL-6 and Gata-3 were not differentially regulated (Fig. 4E).

Bottom Line: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects.Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy.Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.

Research design and methods: To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.

Results: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

Conclusions: Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

Show MeSH
Related in: MedlinePlus