Heterozygous mice for TGF-βIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy

Kim, Hwal Woong; Kim, Bong Cho; Song, Chi Young; Kim, Ji Hoon; Hong, Hye Kyoung; Lee, Hyun Soon

doi:10.1111/j.1523-1755.2004.00959.x

Cited by 30 publications

(28 citation statements)

References 41 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results are also supported by recent results in which renal cells isolated from TGF-␤1 null mice showed impairment in hypertrophy in response to high glucose (71). Additionally, TGF-␤ receptor II heterozygous mice with streptozotocin-induced type 1 diabetes showed significantly reduced glomerular hypertrophy, further providing evidence for the requirement of TGF-␤ signaling (40). However, the mechanism by which TGF-␤ regulates mesangial cell hypertrophy was not elucidated.…”

Section: Discussionsupporting

confidence: 79%

See 1 more Smart Citation

Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN

Mahimainathan¹,

et al. 2006

View full text Add to dashboard Cite

Diabetic nephropathy is characterized early in its course by glomerular hypertrophy and, importantly, mesangial hypertrophy, which correlate with eventual glomerulosclerosis. The mechanism of hypertrophy, however, is not known. Gene disruption of the tumor suppressor PTEN, a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway, in fruit flies and mice demonstrated its role in size control in a cell-specific manner. Here, we investigated the mechanism of mesangial hypertrophy in response to high extracellular glucose. We link early renal hypertrophy with significant reduction in PTEN expression in the streptozotocin-induced diabetic kidney cortex and glomeruli, concomitant with activation of Akt. Similarly, exposure of mesangial cells to high concentrations of glucose also decreased PTEN expression and its phosphatase activity, resulting in increased Akt activity. Expression of PTEN inhibited high-glucose-induced mesangial cell hypertrophy, and expression of dominant-negative PTEN was sufficient to induce hypertrophy. In diabetic nephropathy, the hypertrophic effect of hyperglycemia is thought to be mediated by transforming growth factor-␤ (TGF-␤). TGF-␤ significantly reduced PTEN expression in mesangial cells, with a reduction in its phosphatase activity and an increase in Akt activation. PTEN and dominant-negative Akt attenuated TGF-␤-induced hypertrophy of mesangial cells. Finally, we show that inhibition of TGF-␤ signal transduction blocks the effect of high glucose on PTEN downregulation. These data identify a novel mechanism placing PTEN as a key regulator of diabetic mesangial hypertrophy involving TGF-␤ signaling. Diabetes 55: [2115][2116][2117][2118][2119][2120][2121][2122][2123][2124][2125] 2006

show abstract

Section: Discussionsupporting

confidence: 79%

“…TGF-␤ is a key regulator of diabetic nephropathy (3,5,15). Both TGF-␤ and its type II receptor are increased in the glomeruli of diabetic animals (18,40). Prolonged glucose exposure increases expression of TGF-␤ to mediate the hypertrophic effect.…”

Section: Downregulation Of Pten In Diabetic Nephropathymentioning

confidence: 99%

Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN

Mahimainathan¹,

et al. 2006

View full text Add to dashboard Cite

show abstract

“…For example, TGF␤1 null renal cells display reduced hypertrophy in response to high glucose (44). Furthermore, type 1 diabetic mice heterozygous for the type II TGF␤ receptor exhibit significantly decreased glomerular and mesangial cell hypertrophy, thus reinforcing the requirement of TGF␤-induced signal transduction in this process (45). We and others have shown a pivotal role of mTOR in pathologic renal hypertrophy in vitro and in vivo (14,30,42,46).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β Integrates Smad 3 to Mechanistic Target of Rapamycin Complexes to Arrest Deptor Abundance for Glomerular Mesangial Cell Hypertrophy

Das

Ghosh‐Choudhury

Bera

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Transforming growth factor ␤ (TGF␤) induces renal hypertrophy and fibrosis. Results: TGF␤-induced deptor down-regulation is necessary for prolonged activation of TORC1/2 and mesangial cell hypertrophy. Conclusion: TGF␤-stimulated Smad 3 contributes to deptor suppression and mammalian target of rapamycin activation. Significance: Sustained deptor expression may alleviate renal glomerular hypertrophy and fibrosis.

show abstract

“…A number of studies have shown that TGF-␤ is an important factor in diabetic nephropathy progression through the use of knockout (KO) mouse models for the TGF-␤ type II receptor (9) (which binds TGF-␤1) and TGF-␤ blocking antibodies (10 -12). The investigation of other molecules involved in the regulation of TGF-␤ such as the antifibrogenic peptide bone morphogenic protein 7 (BMP7) (13), which counterbalances TGF-␤ activity and is downregulated in diabetes (14), have also shown efficacy as a strategy for reducing diabetic nephropathy progression (15).…”

mentioning

confidence: 99%

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

et al. 2007

View full text Add to dashboard Cite

Transforming growth factor-␤ (TGF-␤) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-␤1 binding molecule, the soluble human TGF-␤ type II receptor (sT␤RII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-␤1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sT␤RII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sT␤RII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression following sT␤RII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sT␤RII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-␤1-induced disruptions of renal proximal tubule cell uptake of albumin. Diabetes 56:380 -388, 2007

show abstract

Heterozygous mice for TGF-βIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy

Cited by 30 publications

References 41 publications

Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN

Mesangial Cell Hypertrophy by High Glucose Is Mediated by Downregulation of the Tumor Suppressor PTEN

Transforming Growth Factor β Integrates Smad 3 to Mechanistic Target of Rapamycin Complexes to Arrest Deptor Abundance for Glomerular Mesangial Cell Hypertrophy

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Contact Info

Product

Resources

About