Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

Qi, Zhonghua; Fujita, Hiroki; Jin, Jianping; Davis, Linda S.; Wang, Yihan; Fogo, Agnes B.; Breyer, Matthew D.

doi:10.2337/diabetes.54.9.2628

Cited by 262 publications

(309 citation statements)

References 52 publications

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“…We compared two types of diabetic nephropathy from STZ-induced and A-ZIP/F-1 lipoatrophic diabetes mice. We selected commonly regulated genes to minimise interference from the renal toxicity of STZ, genetic background [22] and direct insulin or leptin target molecules [23]. The list of genes commonly upregulated in these two models included proinflammatory and ECM-associated genes and also ones encoding TLRs (ESM Table 4).…”

Section: Resultsmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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Section: Resultsmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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“…Therefore, the aim of this study was to investigate whether the presence or absence of APOE would have an effect on the genes involved in kidney damage in mice. To achieve this, we crossed two strains, B6 and A/J, which are known to be near the extremes of the urinary albumin spectrum for inbred strains (Qi et al 2005; K. DiPetrillo, unpublished results). We used wild-type B6 and A/J mice, which have identical Apoe alleles according to their genome sequence, for the first cross, whereas we used the B6-Apoe À/À knockout mice for the second cross and selected only the homozygous knockout mice in the F 2 population.…”

Section: Discussionmentioning

confidence: 99%

“…To this purpose we performed two independent F 2 intercrosses between C57BL/6J mice, which do not develop albuminuria, and A/J mice, which do develop albuminuria (Qi et al 2005). In the first cross only wild-type inbred 1 strains B6 and A/J were used; in the second cross B6.Apoe À/À animals were crossed to A/J mice and only the Apoe À/À F 2 animals were analyzed.…”

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confidence: 99%

Quantitative Trait Loci for Urinary Albumin in Crosses Between C57BL/6J and A/J Inbred Mice in the Presence and Absence of Apoe

Doorenbos¹,

Tsaih

Sheehan

et al. 2008

Genetics

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We investigated the effect of apolipoprotein E (Apoe) on albuminuria in the males of two independent F 2 intercrosses between C57BL/6J and A/J mice, using wild-type inbred strains in the first cross and B6-Apoe À/À animals in the second cross. In the first cross, we identified three quantitative trait loci (QTL): chromosome (Chr) 2 [LOD 3.5, peak at 70 cM, confidence interval (C.I.) 28-88 cM]; Chr 9 (LOD 2.0, peak 5 cM, C.I. 5-25 cM); and Chr 19 (LOD 1.9, peak 49 cM, C.I. 23-54 cM). The Chr 2 and Chr 19 QTL were concordant with previously found QTL for renal damage in rat and human. The Chr 9 QTL was concordant with a locus found in rat. The second cross, testing only Apoe À/À progeny, did not identify any of these loci, but detected two other loci on Chr 4 (LOD 3.2, peak 54 cM, C.I. 29-73 cM) and Chr 6 (LOD 2.6, peak 33 cM, C.I. 11-61 cM), one of which was concordant with a QTL found in rat. The dependence of QTL detection on the presence of Apoe and the concordance of these QTL with rat and human kidney disease QTL suggest that Apoe plays a role in renal damage.

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“…The Akita C57BL/6J-Ins2 Akita mouse with unilateral nephrectomy was used. 40,41 Potential complications of TGF-␤ antagonism, including inflammation, tumorigenesis, and altered wound healing, were also examined. Akita mice treated for 15 weeks with i.p.…”

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confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy

Cited by 262 publications

References 52 publications

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Quantitative Trait Loci for Urinary Albumin in Crosses Between C57BL/6J and A/J Inbred Mice in the Presence and Absence of Apoe

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

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