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Research Article
Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model
Cristina Martínez-García, Adriana Izquierdo, Vidya Velagapudi, Yurena Vivas, Ismael Velasco, Mark Campbell, Keith Burling, Fernando Cava, Manuel Ros, Matej Orešič, Antonio Vidal-Puig, Gema Medina-Gomez
Disease Models & Mechanisms 2012 5: 636-648; doi: 10.1242/dmm.009266

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Figures

  • Fig. 1.
    Fig. 1.

    Incipient kidney renal injury in POKO mice at 4 weeks of age. (A) Representative immunoblot for p27Kip1 of renal protein from 4-week-old male WT, PPARγ2 KO, ob/ob and POKO mice. Levels were normalized to β-actin. Each value is the optical intensity of each band as a fold induction vs the WT control group (n=6). Fold induction is shown in graphic. *P<0.05 POKO vs ob/ob. (B) Total kidney mRNA levels of different genes from 4-week-old-male mice of each group. Data are means±s.e.m.; n=8–9 in each group; **P<0.01, ***P<0.001 POKO vs ob/ob; #P<0.05 POKO vs WT; $P<0.05 ob/ob vs WT. Normalized levels with BestKeeper (Bk).

  • Fig. 2.
    Fig. 2.

    Ultrastructural changes in the glomeruli of the POKO mice. (A) Transmission electron microscopy of glomeruli of 4-week-old POKO mice with broadening of foot processes (arrows). Foot processes in POKO mice are completely lost by 12 weeks (arrows). Original magnification: 20,000×. (B) GBM thickening in POKO mice when measuring the lamina densa (n=3–4). GBM thicknesses (white star in A) were measured across the whole GBM and across the lamina densa. Data are means±s.e.m.; n=6 in each group; ***P<0.001 POKO vs ob/ob; #P<0.05, ###P<0.001 POKO vs WT; $$P<0.01, $$$P<0.001 ob/ob vs WT.

  • Fig. 3.
    Fig. 3.

    Insulin resistance in POKO kidneys. (A) Total kidney mRNA levels of glucose metabolism genes from 4-week-old male WT, PPARγ2 KO, ob/ob and POKO mice. Data are means±s.e.m.; n=8–9. *P<0.05 POKO vs ob/ob; #P<0.05 POKO vs WT; $P<0.05 ob/ob vs WT; ϕP<0.05 PPARγ2 KO vs WT. Normalized levels with BestKeeper (Bk). (B) Representative immunoblot for pAKT(Ser473) from WT, ob/ob and POKO 4-week-old-male mice treated and non treated with insulin. Levels were normalized to total protein kinase B (AKTt). Each value is the relative optical intensity of each band normalized as a percentage of the saline-treated group. Values are represented in graphic (n=5–8). Data are means±s.e.m. *P<0.05 WT saline vs WT insulin. G6Pase, glucose 6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; IRS, insulin receptor substrate.

  • Fig. 4.
    Fig. 4.

    Altered lipid metabolism in POKO kidneys. (A) Representative Oil-Red-O staining in the kidney from WT, PPARγ2 KO, ob/ob and POKO mice at 4 weeks. Original magnification: 400× (n=4). (B) Intraglomerular electron micrographs of ob/ob mice (12,000×) and POKO mice (15,000×) showing accumulation of lipid droplets (arrows). (C) Total kidney mRNA levels of lipid metabolism genes from 4-week-old male WT, PPARγ2 KO, ob/ob and POKO mice. Data are means±s.e.m.; n=8–9. *P<0.05, **P<0.01, ***P<0.001 POKO vs ob/ob; #P<0.05 POKO vs WT; ϕP<0.05 PPARγ2 KO vs WT. Normalized levels with BestKeeper (Bk).

  • Fig. 5.
    Fig. 5.

    Lipidomic profiling of kidney. (A) The heat map represents log(2) values of the data normalized with the mean of the WT genotype. Lipids with ANOVA P-values<0.05 are shown. 4-week-old male WT, PPARγ2 KO, ob/ob and POKO mice (n=7–8). (B) Differentially regulated lipids between POKO and ob/ob genotypes. P-values *P<0.05, **P<0.005. DG, diacylglycerol; Cer, ceramides; PC, phosphatidylcholine; PE, phosphatidylethanolamine.

  • Fig. 6.
    Fig. 6.

    Inflammation markers and renal injury in the four genotypes. (A) Immunostaining for MCP-1, TGFβ, PTHrP and type IV collagen in the kidney from male WT, PPARγ2 KO, ob/ob and POKO mice at 4 weeks (n=4–5). Original magnification: 400×; scale bars: 50 μm. (B) Representative immunoblot for cytosolic (CE) and nuclear (NE) p65 NFκB protein in renal extracts from WT, PPARγ2 KO, ob/ob and POKO 4-week-old male mice. Levels were normalized to β-actin in the cytosolic fraction and lamin-β receptor in the nuclear fraction. Each value is the relative optical intensity of each band normalized as a percentage of that of the WT group. Values are represented in graphic (n=5–7). Data are means±s.e.m. **P<0.01 POKO vs ob/ob; ##P<0.01 POKO vs WT; ΨP<0.05 POKO vs PPARγ2 KO.

  • Fig. 7.
    Fig. 7.

    Fibrotic markers in the progression of the renal disease in the POKO mice. Representative photomicrographs for PAS staining and Masson’s trichrome staining of kidney sections from male WT, PPARγ2 KO, ob/ob and POKO mice at 4 (A) and 12 (B) weeks. Glomerular fibrosis is shown (arrows) at different ages. Original magnification: 400×. n=4–5.

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Research Article
Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model
Cristina Martínez-García, Adriana Izquierdo, Vidya Velagapudi, Yurena Vivas, Ismael Velasco, Mark Campbell, Keith Burling, Fernando Cava, Manuel Ros, Matej Orešič, Antonio Vidal-Puig, Gema Medina-Gomez
Disease Models & Mechanisms 2012 5: 636-648; doi: 10.1242/dmm.009266
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