Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Kim, Hyosang; Baek, Chung Hee; Lee, Raymond Bok; Chang, Jai Won; Yang, Won Seok; Lee, Sang Koo

doi:10.3390/ijms18020305

Cited by 33 publications

(21 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have suggested the involvement of ER stress in renal fibrosis [23,32,33]. In the present study, we have provided substantial evidence to support a role of ER stress in post-AKI fibrosis.…”

Section: Discussionsupporting

confidence: 80%

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease

et al. 2018

View full text Add to dashboard Cite

BackgroundAcute kidney injury (AKI) may lead to the development of chronic kidney disease (CKD), i.e. AKI-CKD transition, but the underlying mechanism remains largely unclear. Endoplasmic reticulum (ER) stress is characterized by the accumulation of unfolded or misfolded proteins in ER resulting in a cellular stress response. The role of ER stress in AKI-CKD transition remains unknown.MethodsIn this study, we examined ER stress in the mouse model of AKI-CKD transition after unilateral renal ischemia-reperfusion injury (uIR). To determine the role of ER stress in AKI-CKD transition, we tested the effects of two chemical chaperones: Tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA).FindingsuIR led to the induction of ER stress in kidneys, as indicated by increased expression of UPR molecules CHOP (C/EBP homologous protein) and BiP(binding immunoglobulin protein; also called GRP78–78 kDa glucoseregulated protein). Given at 3 days after uIR, both TUDCA and 4-PBA blocked ER stress in post-ischemic kidneys. Notably, both chemicals promoted renal recovery and suppressed tubulointerstitial injury as manifested by the reduction of tubular atrophy, renal fibrosis and myofibroblast activation. Inhibition of ER stress further attenuated renal tubular epithelial cell apoptosis, inflammation and autophagy in post-ischemic kidneys.InterpretationThese findings suggest that ER stress contributes critically to the development of chronic kidney pathologies and CKD following AKI, and inhibition of ER stress may represent a potential therapeutic strategy to impede AKI-CKD transition.

show abstract

Section: Discussionsupporting

confidence: 80%

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In contrast, chronic ER stress can be pro-apoptotic and pro-inflammatory with loss of function: important new evidence links chronic ER stress with fibrotic disease [ 1 , [10] , [11] , [12] , [13] , [14] , [15] ]. ER stress can augment TGF-β signaling, whereas agents that reduce ER stress attenuate fibrosis [ 14 , [16] , [17] , [18] ]. In the kidney, ER stress affects both epithelial and fibroblast compartments and induces apoptosis, mesenchymal phenotype transition, and alters extracellular matrix (ECM) production by tubular epithelium: this is significant since tubular injury is a major determinant of progressive chronic kidney disease [ 11 , [19] , [20] , [21] ].…”

Section: Introductionmentioning

confidence: 99%

Calreticulin is important for the development of renal fibrosis and dysfunction in diabetic nephropathy

Pallero

Owusu

et al. 2020

Matrix Biology Plus

View full text Add to dashboard Cite

Previously, our lab showed that the endoplasmic reticulum (ER) and calcium regulatory protein, calreticulin (CRT), is important for collagen transcription, secretion, and assembly into the extracellular matrix (ECM) and that ER CRT is critical for TGF-β stimulation of type I collagen transcription through stimulation of ER calcium release and NFAT activation. Diabetes is the leading cause of end stage renal disease. TGF-β is a key factor in the pathogenesis of diabetic nephropathy. However, the role of calreticulin ( Calr ) in fibrosis of diabetic nephropathy has not been investigated. In current work, we used both in vitro and in vivo approaches to assess the role of ER CRT in TGF-β and glucose stimulated ECM production by renal tubule cells and in diabetic mice. Knockdown of CALR by siRNA in a human proximal tubular cell line (HK−2) showed reduced induction of soluble collagen when stimulated by TGF-β or high glucose as compared to control cells, as well as a reduction in fibronectin and collagen IV transcript levels. CRT protein is increased in kidneys of mice made diabetic with streptozotocin and subjected to uninephrectomy to accelerate renal tubular injury as compared to controls. We used renal-targeted ultrasound delivery of Cre-recombinase plasmid to knockdown specifically CRT expression in the remaining kidney of uninephrectomized Calr fl/fl mice with streptozotocin-induced diabetes. This approach reduced CRT expression in the kidney, primarily in the tubular epithelium, by 30–55%, which persisted over the course of the studies. Renal function as measured by the urinary albumin/creatinine ratio was improved in the mice with knockdown of CRT as compared to diabetic mice injected with saline or subjected to ultrasound and injected with control GFP plasmid. PAS staining of kidneys and immunohistochemical analyses of collagen types I and IV show reduced glomerular and tubulointerstitial fibrosis. Renal sections from diabetic mice with CRT knockdown showed reduced nuclear NFAT in renal tubules and treatment of diabetic mice with 11R-VIVIT, an NFAT inhibitor, reduced proteinuria and renal fibrosis. These studies identify ER CRT as an important regulator of TGF-β stimulated ECM production in the diabetic kidney, potentially through regulation of NFAT-dependent ECM transcription.

show abstract

“…It is worthy of note that the implication and importance of SIRT1 in kidney-related diseases, such as diabetic nephropathy [ 26 , 32 , 33 , 34 ], acute and chronic kidney disease [ 19 , 35 , 36 ] or lupus nephritis [ 27 , 37 ] can be explained by its involvement in numerous pathways regulation. SIRT1 regulates the TGFβ/Smad and ERK1/2 pathways, also activates metalloproteinases and FOXO1 proteins and controls the NF-kB pathway [ 24 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Decreased Urinary Levels of SIRT1 as Non-Invasive Biomarker of Early Renal Damage in Hypertension

Martínez-Arroyo

Ortega

Galera

et al. 2020

IJMS

View full text Add to dashboard Cite

Sirtuins have become important players in renal damage in hypertension and diabetes, but their value as biomarkers is poorly assessed. The aims of the study were to evaluate the levels of sirtuin1 (SIRT1), and two miRNAs that regulate SIRT1 expression in hypertensive patients with incipient renal damage with and without diabetes. We quantified urinary SIRT1 and claudin 1 (CLDN1) mRNA and miR34-a and miR-200a levels by quantitative real-time polymerase chain reaction (RT-qPCR) from patients and in cultured podocytes treated with high glucose and angiotensin II. Western blot and fluorescence analyses were also performed. We found decreased SIRT1 levels in patients with increased urinary albumin excretion (UAE), the lowest with diabetes presence, and a strong association with UAE, discriminating incipient renal damage. In vitro experiments also showed SIRT1 overall decreases in podocyte cultures under treatment conditions. In urine samples, miR-34a was reduced and miR-200a increased, both related to UAE levels. However, both miRNAs were generally increased in podocyte cultures under high glucose and angiotensin-II treatment. These results show a significant urinary SIRT1 decrease in albuminuric hypertensive patients, strongly associated with albuminuria, suggesting that SIRT1 could be a potential and non-invasive method to assess incipient renal damage in hypertensive patients.

show abstract

Anti-Fibrotic Effect of Losartan, an Angiotensin II Receptor Blocker, Is Mediated through Inhibition of ER Stress via Up-Regulation of SIRT1, Followed by Induction of HO-1 and Thioredoxin

Cited by 33 publications

References 46 publications

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease

Endoplasmic reticulum stress is activated in post-ischemic kidneys to promote chronic kidney disease

Calreticulin is important for the development of renal fibrosis and dysfunction in diabetic nephropathy

Decreased Urinary Levels of SIRT1 as Non-Invasive Biomarker of Early Renal Damage in Hypertension

Contact Info

Product

Resources

About