Dataset Information

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

ABSTRACT:

Background and purpose

Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood.

Experimental approach

C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II.

Key results

Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT₁ receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension.

Conclusions and implications

Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.

SUBMITTER: Xu Z

PROVIDER: S-EPMC6592868 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

Xu Zheng Z Zou Chunpeng C Yu Weihui W Xu Sujing S Huang Lan L Khan Zia Z Wang Jingying J Liang Guang G Wang Yi Y

British journal of pharmacology 20190511 14

<h4>Background and purpose</h4>Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood.<h4>Experimental approach</h4>C57BL/6 ...[more]

PMID: 30958891

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Project description:Background: Qingda granules (QDG) exhibit antihypertension and multiple-target-organ protection. However, the therapeutic potential of QDG on hypertensive renal injury remains unknown. Therefore, the main objective of the current study is to explore the effects and underlying mechanisms of QDG treatment on renal injury in angiotensin (Ang) II-infused mice. Methods and results: Mice were infused with Ang II (500 ng/kg/min) or saline for 4 weeks with subcutaneously implanted osmotic pumps. After infusion, mice in the Ang II + QDG group were intragastrically administrated with QDG daily (1.145 g/kg/day), whereas the control group and Ang II group were intragastrically administrated with the same amount of double-distilled water. Blood pressure of the mice monitored using the CODA™ noninvasive blood pressure system revealed that QDG treatment significantly attenuated elevated blood pressure. Moreover, hematoxylin-eosin staining indicated that QDG treatment ameliorated Ang II-induced renal morphological changes, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilatation. RNA-sequencing (RNA-seq) identified 662 differentially expressed transcripts (DETs) in renal tissues of Ang II-infused mice, which were reversed after QDG treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis based on DETs in both comparisons of Ang II vs. Control and Ang II + QDG vs. Ang II identified multiple enriched pathways, including apoptosis and p53 pathways. Consistently, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining and Annexin V staining revealed that QDG treatment significantly attenuated Ang II-induced cell apoptosis in renal tissues and cultured renal tubular epithelial cell lines (NRK-52E). Furthermore, western blot analysis indicated that Ang II infusion significantly upregulated the protein expression of p53, BCL2-associated X (BAX), cle-caspase-9, and cle-caspase-3, while downregulating the protein expression of BCL-2 in renal tissues, which were attenuated after QDG treatment. Conclusion: Collectively, QDG treatment significantly attenuated hypertensive renal injury, partially by attenuating renal apoptosis and suppressing p53 pathways, which might be the underlying mechanisms.

Project description:BackgroundRenal tubulointerstitial fibrosis is the hallmark of various chronic kidney diseases. Symmetric dimethylarginine (SDMA) is an independent cardiovascular risk factor in patients with chronic kidney diseases, which is mostly excreted through renal tubules. However, the effect of SDMA on kidneys in a pathological condition is currently unknown. In this study, we investigated the role of SDMA in renal tubulointerstitial fibrosis and explored its underlying mechanisms.MethodsMouse unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI) models were established to study renal tubulointerstitial fibrosis. SDMA was injected into kidneys through ureter retrogradely. TGF-β stimulated human renal epithelial (HK2) cells were used as an in vitro model and treated with SDMA. Signal transducer and activator of transcription-4 (STAT4) was inhibited by berbamine dihydrochloride or siRNA or overexpressed by plasmids in vitro. Masson staining and Western blotting were performed to evaluate renal fibrosis. Quantitative PCR was performed to validate findings derived from RNA sequencing analysis.ResultsWe observed that SDMA (from 0.01 to 10 µM) dose-dependently inhibited the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Intrarenal administration of SDMA (2.5 µmol/kg or 25 µmol/kg) dose-dependently attenuated renal fibrosis in UUO kidneys. A significant increase in SDMA concentration (from 19.5 to 117.7 nmol/g, p < 0.001) in mouse kidneys was observed after renal injection which was assessed by LC-MS/MS. We further showed that intrarenal administration of SDMA attenuated renal fibrosis in UIRI induced mouse fibrotic kidneys. Through RNA sequencing analysis, we found that the expression of STAT4 was reduced by SDMA in UUO kidneys, which was further confirmed by quantitative PCR and Western blotting analysis in mouse fibrotic kidneys and renal cells. Inhibition of STAT4 by berbamine dihydrochloride (0.3 mg/ml or 3.3 mg/ml) or siRNA reduced the expression of pro-fibrotic markers in TGF-β stimulated HK2 cells. Furthermore, blockage of STAT4 attenuated the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells. Conversely, overexpression of STAT4 reversed the anti-fibrotic effect of SDMA in TGF-β stimulated HK2 cells.ConclusionTaken together, our study indicates that renal SDMA ameliorates renal tubulointerstitial fibrosis through inhibition of STAT4.

Dataset Information

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Inhibition of STAT3 activation mediated by toll-like receptor 4 attenuates angiotensin II-induced renal fibrosis and dysfunction.

Similar Datasets

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