mTOR Signaling in Kidney Diseases

Gui, Yuan; Dai, Chunsun

doi:10.34067/kid.0003782020

Cited by 20 publications

(13 citation statements)

References 98 publications

(124 reference statements)

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“…Among the many regulatory factors involved in CKD, the mTOR signaling pathway plays an important role in the regulation of inflammatory responses, myofibroblast activation, and deposition during inflammatory conditions [ 12 , 32 ]. Rapamycin, which is an mTOR inhibitor, has shown that it can attenuate inflammation and renal fibrosis in various types of kidney disease [ 33 ]. Additionally, mTOR can modulate the activity of inflammatory transcription factors, including STAT3 [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model

Kim

Gwon

et al. 2022

IJMS

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The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site−targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring−type non−coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)−induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory−related markers (interleukin−1β, tumor necrosis factor−α), and that of fibrosis (α−smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy−related markers, microtubule−associated protein light chain 3, Beclin1, and autophagy−related gene 5−12. We confirmed that ring−type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.

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Section: Discussionmentioning

confidence: 99%

Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model

Kim

Gwon

et al. 2022

IJMS

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“…SLC38A9 (SNAT9) is a sodium coupled AAT located in lysosomes which acts as an arginine sensor to activate mTORC1 [ 53 ] and mediates the efflux of most essential AAs from lysosomes, including leucine, in an arginine-regulated manner [ 54 ]. mTORC1 plays an important role in the regulation of renal cell homeostasis and in the development of several kidney disorders [ 55 ]. On the other hand, kidney plays a central role in arginine metabolism, being the proximal tubule a major site of arginine production from citrulline [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications

et al. 2022

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Type 2 Diabetes (T2D) is a metabolic disease associated with long-term complications, with a multifactorial pathogenesis related to the interplay between genetic and modifiable risk factors, of which nutrition is the most relevant. In particular, the importance of proteins and constitutive amino acids (AAs) in disease susceptibility is emerging. The ability to sense and respond to changes in AA supplies is mediated by complex networks, of which AA transporters (AATs) are crucial components acting also as sensors of AA availability. This study explored the associations between polymorphisms in selected AATs genes and T2D and vascular complications in 433 patients and 506 healthy controls. Analyses revealed significant association of SLC38A3-rs1858828 with disease risk. Stratification of patients based on presence/absence of vascular complications highlighted significant associations of SLC7A8-rs3783436 and SLC38A7-rs9806843 with diabetic retinopathy. Additionally, the SLC38A9-rs4865615 resulted associated with chronic kidney disease. Notably, these genes function as AAs sensors, specifically glutamine, leucine, and arginine, linked to the main nutrient signaling pathway mammalian target of rapamycin complex 1 (mTORC1). Thus, their genetic variability may contribute to T2D by influencing the ability to properly transduce a signal activating mTORC1 in response to AA availability. In this scenario, the contribution of dietary AAs supply to disease risk may be relevant.

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“…In these two studies, Pkd1 or Pkd2 gene was globally knockout, which led to a different baseline, such as, an increased cell proliferation in the kidney of knockout mice as compared with that in wide type mice (14, 20). It has been shown that inhibition of proliferation associated signaling pathways such as the mTOR or MAPK pathway ameliorated renal tubulointerstitial fibrosis (21, 22), and thus the difference in baseline proliferation rate may lead to a different outcome in mouse model of renal fibrosis. To keep the same baseline condition, we only inactivated Pkd gene at one week before kidney injury in this study.…”

Section: Discussionmentioning

confidence: 99%

Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD

Wang

Jing³

et al. 2021

Preprint

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Mutations in PKD2 gene, which encodes polycystin-2, cause autosomal polycystic kidney disease (ADPKD). Development of ADPKD is associated with progression of renal fibrosis. Whether renal fibrosis in ADPKD is a direct effect of polycystin-2 mutation or a consequence of cyst growth induced tubular obstruction is currently unknown. Polycystin-2 has been identified as a direct target of triptolide, and we used triptolide as a probe to study the role of polycystin-2 in renal fibrosis. To study the expression of polycystin-2, we established unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) and aristolochic acid nephropathy mouse models. Here we showed that polycystin-2 is up-regulated in these three mouse models and tightly correlated with the expression of collagen-I in a time dependent manner. Treatment with triptolide inhibited the expression of polycystin-2 and pro-fibrotic markers in UUO and UIRI models. Moreover, triptolide dose-dependently inhibited the expression of polycystin-2 and pro-fibrotic markers in rat renal fibroblasts or in TGF-β stimulated human renal epithelial (HK2) cells. Knockdown of PKD2 reduced the expression of pro-fibrotic markers in TGF-β stimulated or unstimulated HK2 cells. Finally, we showed that knockdown of PKD2 attenuated the inhibitory effect of triptolide on the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells.In conclusion, polycystin-2 is a pro-fibrotic protein suggesting that renal fibrosis in ADPKD kidneys is not a direct effect of PKD2 mutation.

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mTOR Signaling in Kidney Diseases

Cited by 20 publications

References 98 publications

Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model

Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model

The Genetic Variability of Members of the SLC38 Family of Amino Acid Transporters (SLC38A3, SLC38A7 and SLC38A9) Affects Susceptibility to Type 2 Diabetes and Vascular Complications

Tubular obstruction induced polycystin upregulation is pro-fibrotic and induced a severe cystic phenotype in adult mice with autosomal dominant polycystic kidney disease: the coexistence of polycystin loss and gain function in ADPKD

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