Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

Kumar, Vikash; Evans, Louise; Kurth, Theresa; Yang, Chun; Wollner, Clayton; Nasci, Victoria; Zheleznova, Nadezhda N.; Bukowy, John D.; Dayton, Alex; Cowley, Allen W.

doi:10.1161/hypertensionaha.118.12378

Cited by 37 publications

(36 citation statements)

References 36 publications

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“…Dahl salt sensitive rats are widely used to investigate salt-sensitive hypertension, which is characterized by a significant increase in blood pressure after high salt intake. Herein, the rat blood levels increased after 6 weeks of 8% NaCl intake, a result that is consistent with those of previous studies 29,30 , suggesting that the salt-sensitive hypertension model was successfully duplicated. www.nature.com/scientificreports www.nature.com/scientificreports/ Although multiple factors participate in controlling arterial blood pressure, the kidney is a pivotal factor.…”

Section: Discussionsupporting

confidence: 90%

(−)-Epigallocatechin-3-gallate (EGCG) attenuates salt-induced hypertension and renal injury in Dahl salt-sensitive rats

Luo

Chen

et al. 2020

Sci Rep

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Epigallocatechin-3-gallate (EGCG), a main active catechin in green tea, was reported to attenuate renal injury and hypertension. However, its effects on salt-induced hypertension and renal injury remain unclear. In the present study, we explored its effects on hypertension and renal damage in Dahl rats with salt-sensitive hypertension. We found that EGCG could lower blood pressure after 6 weeks of oral administration, reduce 24 h urine protein levels and decrease creatinine clearance, and attenuate renal fibrosis, indicating that it could attenuate hypertension by protecting against renal damage. Furthermore, we studied the renal protective mechanisms of EGCG, revealing that it could lower malondialdehyde levels, reduce the numbers of infiltrated macrophages and T cells, and induce the apoptosis of NRK-49F cells. Considering that the 67 kD laminin receptor (67LR) binds to EGCG, its role in EGCG-induced fibroblast apoptosis was also investigated. The results showed that an anti-67LR antibody partially abrogated the apoptosis-inducing effects of EGCG on NRK-49F cells. In summary, EGCG may attenuate renal damage and salt-sensitive hypertension via exerting anti-oxidant, antiinflammatory, and apoptosis-inducing effects on fibroblasts; the last effect is partially mediated by 67LR, suggesting that EGCG represents a potential strategy for treating salt-sensitive hypertension.Salt-sensitive hypertension is characterized by a significant increase in blood pressure after high salt intake. Patients with this condition are at high risk for cardiovascular and renal morbidity and mortality. Renal injury plays a key role in the pathogenesis of salt sensitive hypertension 1 . Recently, the roles of oxidative stress and inflammatory cell infiltration in the kidney in the pathogenesis of salt-sensitive hypertension were verified 2,3 . Renal fibrosis is a common pathway for a variety of chronic kidney diseases to progress to end-stage renal failure 4 and excessive proliferation of renal interstitial fibroblasts participates in the development of renal fibrosis 5,6 .(−)-Epigallocatechin-3-gallate (EGCG) is the most active and abundant polyphenol in green tea, accounting for approximately 50% of green tea polyphenols 7 . Recently, EGCG has attracted interest due to its wide range of biological activities, such as its antioxidant, NO-scavenging, anti-inflammatory, anti-arthritic and apoptosis-inducing effects in multiple types of tumour cells 8,9 . EGCG benefits a broad spectrum of hypertension disorders, including renovascular hypertension 10 and spontaneous hypertension 11 . The renoprotective effect of EGCG has been reported in several renal disease models 12 , such as acute kidney injury 13 , cisplatin-induced nephrotoxicity 14 , obstructive nephropathy 15 , glomerulonephritis 16 , lupus nephritis 17 , diabetic nephropathy 18 , and high-fat diet-induced kidney injury 19 . However, the effects of EGCG on salt-induced hypertension and renal injury remain unclear.

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Section: Discussionsupporting

confidence: 90%

(−)-Epigallocatechin-3-gallate (EGCG) attenuates salt-induced hypertension and renal injury in Dahl salt-sensitive rats

Luo

Chen

et al. 2020

Sci Rep

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“…The glomerular damage score was 1.8 ± 0.1 vs. 3.2 ± 0.1 in the NS and HS diet fed groups, respectively. Therefore, the welldeveloped renal injury and BP increase in our model were in accordance with previously published studies (Endres et al, 2017;Palygin et al, 2017;Pavlov et al, 2017;Ilatovskaya et al, 2018;Kumar et al, 2019).…”

Section: Hypertension and Renal Injury Development In Dahl Ss Ratssupporting

confidence: 92%

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

et al. 2020

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Salt-sensitive (SS) hypertension is accompanied with an early onset of proteinuria, which results from the loss of glomerular podocytes. Here, we hypothesized that glomerular damage in the SS hypertension occurs in part due to mitochondria dysfunction, and we used a unique model of freshly isolated glomeruli to test this hypothesis. In order to mimic SS hypertension, we used Dahl SS rats, an established animal model. Animals were fed a 0.4% NaCl (normal salt, NS) diet or challenged with a high salt (HS) 4% NaCl diet for 21 days to induce an increase in blood pressure (BP). Similar to previous studies, we found that HS diet caused renal hypertrophy, increased BP, glomerulosclerosis, and renal lesions such as fibrosis and protein casts. We did not observe changes in mitochondrial biogenesis in the renal cortex or isolated glomeruli fractions. However, Seahorse assay performed on freshly isolated glomeruli revealed that basal mitochondrial respiration, maximal respiration, and spare respiratory capacity were lower in the HS compared to the NS group. Using confocal imaging and staining for mitochondrial H 2 O 2 using mitoPY1, we detected an intensified response to an acute H 2 O 2 application in the podocytes of the glomeruli isolated from the HS diet fed group. TEM analysis showed that glomerular mitochondria from the HS diet fed group have structural abnormalities (swelling, enlargement, less defined cristae). Therefore, we report that glomerular mitochondria in SS hypertension are functionally and structurally defective, and this impairment could eventually lead to loss of podocytes and proteinuria. Thus, the glomerular-mitochondria axis can be targeted in novel treatment strategies for hypertensive glomerulosclerosis.

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“…However, improper control of mTORC1 activity during these early stages can lead to hypertrophic cardiomyopathy. Inhibition of mTORC1 or reduction of mTORC1 substrate activity can facilitate prevention of cardiac hypertrophy [ 12 , 13 , 19 , 24 ]; recently, inhibition of mTORC2 activity has also been shown to prevent hypertension and kidney injury in a rat model [ 25 ]. Therefore, inhibition of mTORC1 is an important approach for prevention of cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

Quan

Zhang

et al. 2020

Redox Biology

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Sestrin2 (Sesn2) is a stress sensor for the mammalian target of rapamycin complex 1 (mTORC1) pathway. Aging impairs cardiac mTORC1 activation, thereby sensitizing the heart to hypertrophy. C57BL/6 J young wild-type (young WT; 4–6 months), aged WT (24–26 months), and young Sestrin2 knockout mice (Y-Sesn2 KO; 4–6 months) underwent transverse aortic constriction (TAC) for pressure overload. Cardiac expression of Sesn2 decreased with age. At 4 weeks after TAC, aged WT and Y-Sesn2 KO exhibited larger hearts and impaired cardiac function, compared with young WT mice. Augmented phosphorylation of mTOR and downstream effectors; damaged mitochondria and elevated redox markers, as well as and impaired glucose and fatty acid oxidation were observed in aged WT and Y-Sesn2 KO hearts. A pressure overload-induced interaction between Sesn2 and GTPase-activating protein activity toward Rags 2 (GATOR2), which positively regulates mTORC1, was impaired in aged WT hearts. Adeno-associated virus 9–Sesn2 treatment rescued Sesn2 expression, attenuated mTORC1 activation, and increased pressure overload tolerance in aged WT and Y-Sesn2 KO hearts. These results indicated that cardiac Sesn2 acts as a pressure overload sensor for mTORC1. Furthermore, Sesn2 deficiency may cause increased sensitivity to hypertrophy in elderly individuals.

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Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

Cited by 37 publications

References 36 publications

(−)-Epigallocatechin-3-gallate (EGCG) attenuates salt-induced hypertension and renal injury in Dahl salt-sensitive rats

(−)-Epigallocatechin-3-gallate (EGCG) attenuates salt-induced hypertension and renal injury in Dahl salt-sensitive rats

Renal Glomerular Mitochondria Function in Salt-Sensitive Hypertension

Substrate metabolism regulated by Sestrin2–mTORC1 alleviates pressure overload-induced cardiac hypertrophy in aged heart

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