Rheb/mTORC1 Signaling Promotes Kidney Fibroblast Activation and Fibrosis

Jiang, Lei; Xu, Lingling; Mao, Junhua; Li, Jianzhong; Li, Fang; Zhou, Yang; Liu, Wei; He, Weichun; Zhao, Allan Z.; Yang, Junwei; Dai, Chunsun

doi:10.1681/asn.2012050476

Cited by 80 publications

(91 citation statements)

References 63 publications

(82 reference statements)

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“…(14,18,22). We showed here that blocking mTORC1 signaling with rapamycin could not only inhibit new cellular crescent formation but also abolish those crescents established in the glomeruli at the beginning of the treatment.…”

Section: Discussionmentioning

confidence: 73%

“…mTORC1 is negatively regulated by Tsc1/Tsc2 through inhibiting Rheb. Abnormal activation of mTORC1 participates in the pathogenesis of many types of kidney disease, including polycystic kidney disease, diabetic nephropathy (12,18,22,25), podocyte dysfunction, glomerular sclerosis, and kidney fibrosis (4,10,11,14,15,27,30). However, whether mTORC1 signaling activation in podocytes contributes to crescent formation remains obscure.…”

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confidence: 99%

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Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

Mao

Zeng

et al. 2014

American Journal of Physiology-Renal Physiology

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Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

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Section: Discussionmentioning

confidence: 73%

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confidence: 99%

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

Mao

Zeng

et al. 2014

American Journal of Physiology-Renal Physiology

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“…29 In addition, the activation of mTOR also occurs in a variety of animal models of diabetic nephropathy and other progressive CKD. [39][40][41] We hypothesized that KIM-1-induced injury may involve mTOR pathway activation, which could contribute to kidney fibrosis and progressive CKD. In the zebrafish, we observed that the expression of kim-1 was associated with mTOR activation, and that the mTOR inhibitor, rapamycin, protected against kim-1-induced injury.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Yin¹,

Naini²,

Chen³

et al. 2015

JASN

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Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.

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“…Meanwhile, the epithelial-mesenchymal transition (EMT), a major mechanism of tubulointerstitial fibrosis [11,12], is tightly associated with mTOR activity. Rapamycin (Rap), an mTOR signaling inhibitor, exerts an anti-fibrosis effect in many tissue fibrosis diseases [13,14,15]. However, whether Rap exerts a renoprotective effect in Aldo-induced renal injury has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang

Ding

Zhang

et al. 2015

Cell Physiol Biochem

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Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

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Rheb/mTORC1 Signaling Promotes Kidney Fibroblast Activation and Fibrosis

Cited by 80 publications

References 63 publications

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

Mammalian Target of Rapamycin Mediates Kidney Injury Molecule 1-Dependent Tubule Injury in a Surrogate Model

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

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