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. 2015 Sep 30;27(5):1362–1378. doi: 10.1681/ASN.2014121271

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Copyright © 2016 by the American Society of Nephrology

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Figure 5. — TGR5 specific agonist INT-777 prevents nephropathy in diet-induced obesity mice. (A) TGR5 mRNA expression is decreased in the kidneys of mice with diet-induced obesity. (B) Urinary albumin excretion is increased in mice fed a high fat (HF) diet and treatment with INT-777 decreases albuminuria. (C) Nephrin immunofluorescence microscopy shows that the percentage of podocyte marker nephrin positive area in glomerular tuft, indicative of podocyte density, is restored by the treatment with INT-777 in db/db kidneys. (D) Fibronectin immunofluorescence microscopy indicates marked accumulation of glomerular matrix in HF mice and treatment with INT-777 results in a significant decrease in fibronectin immunostaining. (E) Type IV collagen immunofluorescence microscopy indicates that the marked accumulation of glomerular matrix in HF mice is significantly decreased by the treatment with INT-777. (F) Profibrotic growth factors TGF-β, CTGF, and PAI-1 expression are increased in HF diet and treatment with INT-777 results in marked decreases in the expression of these profibrotic growth factors. (G) CD68 immunofluorescence microscopy indicates significant increase in immunostaining in HF mice, which is indicative of increased macrophage accumulation, and treatment with INT-777 results in decrease of CD68 immunostaining. (H) Proinflammatory cytokines MCP-1, TLR2, and TLR4 expression are increased in HF diet and treatment with INT-777 results in marked decreases in the expression of these proinflammatory cytokines. (I) Coherent anti-stokes Raman scattering (CARS) microscopy imaging indicates increased lipid accumulation in the kidneys of HF mice and treatment with INT-777 results in decreased lipid accumulation. (J and K) Representative Western blots show that INT-777 treatment increases expression of mediators of mitochondrial biogenesis, including p-AMPK (J), PGC-1α and SIRT3 (K). Increased SIRT3 expression with the INT-777 treatment is further manifested by immunofluorescence (L, green SIRT3, red F-actin). (M) Treatment of HF mice with INT-777 induced increased mitochondrial SOD protein. (N) Average caloric intake shows no difference in HF mice with INT-777 treatment from HF mice without treatment.

Figure 5. — TGR5 specific agonist INT-777 prevents nephropathy in diet-induced obesity mice. (A) TGR5 mRNA expression is decreased in the kidneys of mice with diet-induced obesity. (B) Urinary albumin excretion is increased in mice fed a high fat (HF) diet and treatment with INT-777 decreases albuminuria. (C) Nephrin immunofluorescence microscopy shows that the percentage of podocyte marker nephrin positive area in glomerular tuft, indicative of podocyte density, is restored by the treatment with INT-777 in db/db kidneys. (D) Fibronectin immunofluorescence microscopy indicates marked accumulation of glomerular matrix in HF mice and treatment with INT-777 results in a significant decrease in fibronectin immunostaining. (E) Type IV collagen immunofluorescence microscopy indicates that the marked accumulation of glomerular matrix in HF mice is significantly decreased by the treatment with INT-777. (F) Profibrotic growth factors TGF-β, CTGF, and PAI-1 expression are increased in HF diet and treatment with INT-777 results in marked decreases in the expression of these profibrotic growth factors. (G) CD68 immunofluorescence microscopy indicates significant increase in immunostaining in HF mice, which is indicative of increased macrophage accumulation, and treatment with INT-777 results in decrease of CD68 immunostaining. (H) Proinflammatory cytokines MCP-1, TLR2, and TLR4 expression are increased in HF diet and treatment with INT-777 results in marked decreases in the expression of these proinflammatory cytokines. (I) Coherent anti-stokes Raman scattering (CARS) microscopy imaging indicates increased lipid accumulation in the kidneys of HF mice and treatment with INT-777 results in decreased lipid accumulation. (J and K) Representative Western blots show that INT-777 treatment increases expression of mediators of mitochondrial biogenesis, including p-AMPK (J), PGC-1α and SIRT3 (K). Increased SIRT3 expression with the INT-777 treatment is further manifested by immunofluorescence (L, green SIRT3, red F-actin). (M) Treatment of HF mice with INT-777 induced increased mitochondrial SOD protein. (N) Average caloric intake shows no difference in HF mice with INT-777 treatment from HF mice without treatment.