Dojuksan ameliorates tubulointerstitial fibrosis through irisin-mediated muscle-kidney crosstalk

Jiang, Songling; Oh, Dal‐Seok; Dorotea, Debra; Son, Eunjung; Kim, Dong Seon; Ha, Hunjoo

doi:10.1016/j.phymed.2020.153393

Cited by 13 publications

(12 citation statements)

References 37 publications

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“…Our previous studies have established an obstruction-induced tubulointerstitial fibrosis model in rat and mice [ 12 , 32 ]. Based on these analyses, mice were administered LJ-4459 to start 1 d prior to UUO surgery and all mice were euthanized after 7 d of treatment ( Figure 1 A).…”

Section: Resultsmentioning

confidence: 99%

“…We examined the effect of LJ-4459 on kidney dysfunction and kidney tubular injury in the obstructed kidneys. Plasma creatinine and blood urea nitrogen (BUN), markers of kidney injury, were significantly increased in UUO mice [ 32 ]. Plasma creatinine was effectively reduced by 10 mg/kg LJ-4459 treatment ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

“…The 6-week-old male C57BL/6J mice were purchased from the Ewha Laboratory Animal Genomic center (Seoul, Korea). Unilateral ureteral obstruction (UUO) surgery was performed as described in our previous study [ 12 , 32 ]. Mice were housed in a room maintained at 22 ± 2 °C with a 12 h dark/12 h light cycle and were randomly divided into three groups: (i) UUO without LJ-4459 treatment (0 mg/kg), (ii) UUO+LJ-4459 1 mg/kg, and (iii) UUO+LJ-4459 10 mg/kg.…”

Section: Methodsmentioning

confidence: 99%

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Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice

Pak

Jeong

Hou

et al. 2021

IJMS

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Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), A1AR, A2AAR, A2BAR, and A3AR. A2AAR agonists protect against inflammation, and A3AR antagonists effectively inhibit the formation of fibrosis. Here, we showed for the first time that LJ-4459, a newly synthesized dual-acting ligand that is an A2AAR agonist and an A3AR antagonist, prevents the progression of tubulointerstitial fibrosis. Unilateral ureteral obstruction (UUO) surgery was performed on 6-week-old male C57BL/6 mice. LJ-4459 (1 and 10 mg/kg) was orally administered for 7 days, started at 1 day before UUO surgery. Pretreatment with LJ-4459 improved kidney morphology and prevented the progression of tubular injury as shown by decreases in urinary kidney injury molecular-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) excretion. Obstruction-induced tubulointerstitial fibrosis was attenuated by LJ-4459, as shown by a decrease in fibrotic protein expression in the kidney. LJ-4459 also inhibited inflammation and oxidative stress in the obstructed kidney, with reduced macrophage infiltration, reduced levels of pro-inflammatory cytokines, as well as reduced levels of reactive oxygen species (ROS). These data demonstrate that LJ-4459 has potential as a therapeutic agent against the progression of tubulointerstitial fibrosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice

Pak

Jeong

Hou

et al. 2021

IJMS

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“…Thus, the current study strongly revealed the molecular mechanism in which Bmal1 modulates renal fibrosis via direct upregulation of Gli2 and highlighted the importance of circadian rhythm in renal fibrosis. Despite all this, growing evidence have indicated that hypertension is an important cause of chronic kidney diseases and many antihypertensive medicines have shown anti‐fibrotic and reno‐protective effects 47‐50 . Since our data displayed significant hypotensive phenotype of the iKO mice, thus there is possibility that the blood pressure lowering might potentially contribute to the phenotypic changes in renal fibrosis as well.…”

Section: Discussionmentioning

confidence: 60%

“…Despite all this, growing evidence have indicated that hypertension is an important cause of chronic kidney diseases and many antihypertensive medicines have shown anti-fibrotic and reno-protective effects. [47][48][49][50] Since our data displayed significant hypotensive phenotype of the iKO mice, thus there is possibility that the blood pressure lowering might potentially contribute to the phenotypic changes in renal fibrosis as well. Dissecting the contribution of Bmal1 to blood pressure and renal fibrosis is worth further exploration.…”

Section: Discussionmentioning

confidence: 81%

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

et al. 2021

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Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-β increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.

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Chronic kidney disease-induced muscle atrophy: Molecular mechanisms and promising therapies

Wang

Qing-yuan

Tang

et al. 2023

Biochemical Pharmacology

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Dojuksan ameliorates tubulointerstitial fibrosis through irisin-mediated muscle-kidney crosstalk

Cited by 13 publications

References 37 publications

Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice

Dual Actions of A2A and A3 Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice

Postnatal deletion of Bmal1 in mice protects against obstructive renal fibrosis via suppressing Gli2 transcription

Chronic kidney disease-induced muscle atrophy: Molecular mechanisms and promising therapies

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