The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential

Mori, Hiroyuki; Inoki, Ken; Masutani, Kohsuke; Wakabayashi, Yu; Komai, Kyoko; Nakagawa, Ryusuke; Guan, Kun Liang; Yoshimura, Akihiko

doi:10.1016/j.bbrc.2009.04.136

Cited by 149 publications

(124 citation statements)

References 16 publications

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“…Although they affect many pathways besides autophagy, several studies have shown that these treatments have positive effects on inflammation, tubular injury, glomerulosclerosis, and podocyte injury in rodent models of DN. [73][74][75][76][77][78][79][80] Interestingly, Wen et al show that the treatment of diabetic mice with resveratrol impairs intraglomerular capillary rarefaction, suggesting that resveratrol attenuates diabetic nephropathy by modulating lox/lox control, Atg5 lox/lox control diabetic, Cdh5.Cre-atg5 lox/lox control and Cdh5.Cre-atg5 lox/lox diabetic mice. Data represent means §SEM of 3 (nondiabetic) or 4 (diabetic) mice.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

et al. 2015

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filtration barrier; MAP1LC3A/B/LC3A/B), microtubule-associated protein 1 light chain 3 a/b; MTOR, mechanistic target of rapamycin; Nphs2, nephrosis 2, podocin; SQSTM1, sequestosome 1; STZ, streptozotocin; TEM, transmission electron microscopy; TUBA, tubulin; a, WT1, Wilms tumor 1.The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelialspecific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.

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Section: Discussionmentioning

confidence: 99%

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

et al. 2015

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“…Although many studies have shown that mTORC1 is involved in glomerular hypertrophy [9,32,33], there has been limited evidence supporting the involvement of this pathway in podocyte hypertrophy in DN. However, recent studies have shown that mTORC1 effectors are upregulated in the podocytes of diabetic glomeruli, and podocytespecific mTORC1 inhibition attenuates not only diabetesinduced podocyte hypertrophy but also glomerulosclerosis [10,34].…”

Section: Discussionmentioning

confidence: 99%

“…Diabetes-induced podocyte hypertrophy requires G 1 /S cell-cycle arrest mediated by cyclin-dependent kinase inhibitors (CKIs) [5,8]. In addition, the activation of mTOR complex 1 (mTORC1) and its downstream effectors, including eukaryotic elongation factor 4E-binding-protein-1 (4EBP1) and p70S6 kinase (p70S6K), play a pivotal role in diabetes-induced podocyte hypertrophy [9,10].…”

Section: Introductionmentioning

confidence: 99%

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

Kim

Nam

et al. 2012

Diabetologia

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Aims/hypothesis Translationally controlled tumour protein (TCTP) is thought to be involved in cell growth by regulating mTOR complex 1 (mTORC1) signalling. As diabetes characteristically induces podocyte hypertrophy and mTORC1 has been implicated in this process, TCTP may have a role in the pathogenesis of diabetes-induced podocyte hypertrophy. Methods We investigated the effects and molecular mechanisms of TCTP in diabetic mice and in high glucose-stimulated cultured podocytes. To characterise the role of TCTP, we conducted lentivirus-mediated gene silencing of TCTP both in vivo and in vitro. Results Glomerular production of TCTP was significantly higher in streptozotocin induced-diabetic DBA/2J mice than in control animals. Double-immunofluorescence staining for TCTP and synaptopodin revealed that podocyte was the principal cell responsible for this increase. TCTP knockdown attenuated the activation of mTORC1 downstream effectors and the overproduction of cyclin-dependent kinase inhibitors (CKIs) in diabetic glomeruli, along with a reduction in proteinuria and a decrease in the sizes of podocytes as well as glomeruli. In addition, knockdown of TCTP in db/db mice prevented the development of diabetic nephropathy, as indicated by the amelioration of proteinuria, mesangial expansion, podocytopenia and glomerulosclerosis. In accordance with the in vivo data, TCTP inhibition abrogated high glucose-induced hypertrophy in cultured podocytes, which was accompanied by the downregulation of mTORC1 effectors and CKIs. Conclusions/interpretation These findings suggest that TCTP might play an important role in the process of podocyte hypertrophy under diabetic conditions via the regulation of mTORC1 activity and the induction of cell-cycle arrest.

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“…As it was previously demonstrated, in some tissues, i.e. mesangial cells or in renal cortex [11,12] the sensitivity of mTOR/p70-S6K pathway is preserved in insulin resistance and this pathway is being continuously over-stimulated due to the persisting hyperinsulinemia. Nevertheless, insulin signalling was significantly attenuated in white adipose tissue of HHTg rats ( Figure 3).…”

Section: Adipose Tissue Heparin-releasable Lpl Activity Is Higher In mentioning

confidence: 71%

“…Recent reports show that the effect of chronic hyperinsulinemia is tissue-specific. p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice [11] and in the renal cortex of Zucker diabetic rats [12] and it is supposed to contribute to the renal hyperplasia. On the other hand, chronic hyperinsulinemia imposed on normal rats (5 days hyperinsulinemic-euglycemic clamp) had no effect on mTOR/p70-S6K pathway in white adipose tissue [9].…”

Section: Introductionmentioning

confidence: 99%

Nutritional regulation of adipose tissue lipoprotein lipase is blunted in insulin resistant rats

et al. 2012

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Background:Hypertriglyceridemia is a common lipid abnormality accompanying insulin resistance. This study was designed to assess the contribution of dysregulation of adipose tissue lipoprotein lipase (LPL) activity to the hypertriglyceridemia in a rat model of insulin resistance. Methodology: Hereditary hypertriglyceridemic (HHTg) rats were challenged for two weeks on a high sucrose diet and LPL activity, angptl-4 expression and FFA utilisation in vitro were determined in adipose tissue. Results: Compared to control rats (Wistar), HHTg rats exhibited hyperinsulinemia, impaired fatty acid storage in adipose tissue and elevated LPL activity both in fasting and after refeeding. The expression of angiopoietin-like protein 4 (angptl4), a fastinginduced control protein for LPL activity, was not increased in adipose tissue of fasted HHTg rats as it was in the control rats. Conclusion: We conclude that LPL remains in its active form to a higher extent in HHTg rat adipose tissue due to the low expression of angptl4 on fasting. This is a possible consequence of the hyperinsulinemia. In combination with the impaired storage of fatty acids as triglycerides in adipose tissue in HHTg rats, the inflexibility of angptl4 expression may contribute to the establishment of hypertriglyceridemia in the insulin-resistant animals.

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The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential

Cited by 149 publications

References 16 publications

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes

Nutritional regulation of adipose tissue lipoprotein lipase is blunted in insulin resistant rats

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