Activation of renal signaling pathways in db/db mice with type 2 diabetes

Féliers, Denis; Duraisamy, Senthil; Faulkner, Jennifer L.; Duch, John; Lee, Adrian V.; Abboud, Hanna E.; Choudhury, Goutam Ghosh; Kasinath, Balakuntalam S.

doi:10.1046/j.1523-1755.2001.060002495.x

Cited by 96 publications

(82 citation statements)

References 36 publications

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“…In spite of these endocrine dissimilarities between models of type 1 and type 2 diabetes, local renal changes in type 2 diabetes mellitus are similar to those found in type 1 diabetes mellitus (renal and glomerular hypertrophy, hyperfiltration, albuminuria) [24]. In both models changes can be seen after a similar short period of hyperglycaemia.…”

Section: Discussionmentioning

confidence: 50%

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

et al. 2007

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Aims/hypothesis In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. Materials and methods Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.Results Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulinlike growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulindriven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. Conclusions/interpretation Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.

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Section: Discussionmentioning

confidence: 50%

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

et al. 2007

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“…In a type 2 diabetic model, ERK activity was reported to be significantly activated in renal cortex of db/db mice as compared with non-diabetic mice 29 . ERK activation may well be due to upstream PKC activation as PKC inhibition also inhibits ERK activation 30 .…”

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confidence: 98%

Regulation of Transforming Growth Factor β in Diabetic Nephropathy: Implications for Treatment

Zhu¹,

Usui²,

Sharma³

2007

Seminars in Nephrology

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The recognition of the drivers of matrix accumulation as a therapeutic target for diabetic nephropathy is accepted by the Nephrology and pharmaceutical community. Interventions focused around Transforming Growth Factor-beta (TGF-β) will likely be an important area of clinical investigation in the near future. Understanding the various pathways involved in stimulating TGF-β in the diabetic kidney is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. In this review we highlight the major pathways involved in stimulating TGF-β production by elevated glucose and discuss the therapeutic implications.

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“…We and others have shown a significant role of this kinase cascade in inducing renal hypertrophy and matrix expansion in diabetic animals and in cultured mesangial and proximal tubular epithelial cells (5)(6)(7)(8)(9)(10). Our recent observation that hyperglycemia reduces the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10), which acts as a lipid phosphatase to dephosphorylate the PI 3,4,5-trisphosphate, also contributes to the hyperactivation of Akt in diabetic renal glomeruli and in mesangial cells, therefore providing an additional mechanism of Akt activation in diabetic kidney disease (7,11).…”

mentioning

confidence: 99%

High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression

Das

Ghosh‐Choudhury

Dey

et al. 2014

Journal of Biological Chemistry

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Activation of renal signaling pathways in db/db mice with type 2 diabetes

Abstract: These studies demonstrate that a variety of receptor signaling pathways are activated in the renal cortex of mice with type 2 diabetes, and suggest a role for augmented insulin receptor activity in nephropathy of type 2 diabetes.

Cited by 96 publications

References 36 publications

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

Regulation of Transforming Growth Factor β in Diabetic Nephropathy: Implications for Treatment

High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression

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