STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model

Yokota, Tsutomu; Omachi, Kohei; Suico, Mary Ann; Kamura, Misato; Kojima, Haruka; Fukuda, Ryosuke; Motomura, K.; Teramoto, Keisuke; Kaseda, Shota; Kuwazuru, Jun; Tanaka, Takeo; Nakagata, Naomi; Shuto, Tsuyoshi; Kai, Hirofumi

doi:10.1093/ndt/gfx246

Cited by 25 publications

(34 citation statements)

References 33 publications

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“…Glomerular dysfunction and resulting albuminuria further stimulates proximal tubule damage and eventual fibrosis, which progresses to renal failure (72). Yokota et al (103) investigated STAT3 activation in Alport syndrome and found increased pSTAT3 (Tyr 705 ) in both isolated glomeruli and the renal cortex of a mouse model of Alport syndrome, with accompanying increases in proinflammatory STAT3 target genes (Table 1). They tested whether or not STAT3 inhibition could ameliorate renal dysfunction in a mouse model of Alport syndrome.…”

Section: Alport Syndromementioning

confidence: 99%

Targeting STAT3 signaling in kidney disease

Pace

Paladugu

Das

et al. 2019

American Journal of Physiology-Renal Physiology

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The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.

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Section: Alport Syndromementioning

confidence: 99%

Targeting STAT3 signaling in kidney disease

Pace

Paladugu

Das

et al. 2019

American Journal of Physiology-Renal Physiology

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“…STAT3 and IL6 were found to be increased in mice with Alport syndrome before anti-miR-21 treatment; the group, therefore, investigated the impact of STAT3 and IL6 inhibitors in Alport mice. They found that STAT3 inhibition reduced proteinuria, whereas IL6 inhibition had no effect on this metric of glomerular function [39]. This is not the only treatment that the group have tested in Alport mice; bromide supplementation was also tried, as Billy Hudson had shown bromide to be important for type IV collagen network formation [40].…”

Section: Basic Sciencementioning

confidence: 99%

The importance of clinician, patient and researcher collaborations in Alport syndrome

et al. 2019

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Alport syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.

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“…LLC., USA) following the recommended protocol. To evaluate the glomerulosclerosis severity, more than 50 random glomeruli per mouse were scored based on the following criteria as reported previously 43 , 0: no lesion, 1: expansion of mesangial area, 2: expansion of Bowman’s epithelial cells, adhesion of glomeruli and Bowman’s capsule and partial sclerosis, 3: sclerotic area in 50–75% of glomeruli, and 4: sclerotic area in 75–100% of glomeruli. In addition, 10 random fields per mouse were captured and protein cast area (%) was calculated by the ratio to tissue area.…”

Section: Methodsmentioning

confidence: 99%

Mild electrical stimulation with heat shock attenuates renal pathology in adriamycin-induced nephrotic syndrome mouse model

Teramoto

Tsurekawa

Suico

et al. 2020

Sci Rep

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Nephrotic syndrome (NS) is a renal disorder that is characterized by massive proteinuria, hypoalbuminemia and edema. One of the main causes of NS is focal segmental glomerulosclerosis (FSGS), which has extremely poor prognosis. Although steroids and immunosuppressants are the first line of treatment, some FSGS cases are refractory, prompting the need to find new therapeutic strategies. We have previously demonstrated that an optimized combination treatment of mild electrical stimulation (MES) and heat shock (HS) has several biological benefits including the amelioration of the pathologies of the genetic renal disorder Alport syndrome. Here, we investigated the effect of MES + HS on adriamycin (ADR)-induced NS mouse model. MES + HS suppressed proteinuria and glomerulosclerosis induced by ADR. The expressions of pro-inflammatory cytokines and pro-fibrotic genes were also significantly downregulated by MES + HS. MES + HS decreased the expression level of cleaved caspase-3 and the number of TUNEL-positive cells, indicating that MES + HS exerted anti-apoptotic effect. Moreover, MES + HS activated the Akt signaling and induced the phosphorylation and inhibition of the apoptotic molecule BAD. In in vitro experiment, the Akt inhibitor abolished the MES + HS-induced Akt-BAD signaling and anti-apoptotic effect in ADR-treated cells. Collectively, our study suggested that MES + HS modulates ADR-induced pathologies and has renoprotective effect against ADR-induced NS via regulation of Akt-BAD axis.

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STAT3 inhibition attenuates the progressive phenotypes of Alport syndrome mouse model

Abstract: STAT3 inhibition significantly ameliorated the renal dysfunction in AS mice. Our finding identifies STAT3 as an important regulator in AS progression and provides a promising therapeutic target for AS.

Cited by 25 publications

References 33 publications

Targeting STAT3 signaling in kidney disease

Targeting STAT3 signaling in kidney disease

The importance of clinician, patient and researcher collaborations in Alport syndrome

Mild electrical stimulation with heat shock attenuates renal pathology in adriamycin-induced nephrotic syndrome mouse model

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