STAT3 inhibition ameliorates renal interstitial inflammation in MRL/lpr mice with diffuse proliferative lupus nephritis

Abstract

Background and objectives

Acute kidney injury (AKI) is one of the most common and severe clinical syndromes of diffuse proliferative lupus nephritis (DPLN), of which poor prognosis is indicated by aggravated renal function deterioration. However, the specific therapy and mechanisms of AKI in DPLN remain to be explored.

Methods

The correlation between AKI and clinical pathological changes in DPLN patients was analyzed. Expression of STAT3 signaling was detected in MRL/lpr mice with DPLN using immunohistochemical staining and immunoblotting. Inhibition of STAT3 activation by combination therapy was assessed in MRL/lpr mice.

Results

Correlation analysis revealed only the interstitial leukocytes were significantly related to AKI in endocapillary DPLN patients. MRL/lpr mice treated with vehicle, which can recapitulate renal damages of DPLN patients, showed upregulation of STAT3, pSTAT3 and caspase-1 in renal cortex. FLLL32 combined with methylprednisolone therapy significantly inhibited the STAT3 activation, improved acute kidney damage, reduced the interstitial infiltration of inflammatory cells and decreased the AKI incidence in MRL/lpr mice.

Conclusion

STAT3 activation may play an important role in the pathogenesis of DPLN and the development of AKI. Hence, STAT3 inhibition based on the combination of FLLL32 with methylprednisolone may represent a new strategy for treatment of DPLN with AKI.

Keywords:

• STAT3
• AKI
• lupus nephritis
• renal interstitial

Acknowledgments

We thank Zhouqing Huang and Tingting Wang, Fanfan Li, Mo Shen, Xinxin Zhou, Keqing Shi and Jinrong Tian for technical assistance.

Ethical approval

The DPLN clinical study was approved by Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University with a waiver of the need for an informed consent. Animal studies were approved by the Wenzhou Medical University Institutional Animal Care Committee.

Author contributions

TXC conceived study. JFZ collected animal renal tissue and blood sample. TXC, JFZ, YJC and YLC wrote the manuscript. TXC analyzed experimental data and interpreted results. YQL reviewed pathological image. All authors contributed to the article and approved the submitted version.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The raw data supporting the conclusions of this article will be made available by the corresponding author, without undue reservation.

Additional information

Funding

This research was supported by the Joint Constructive Project of National Administration of Traditional Chinese Medicine and Zhejiang Administration of Traditional Chinese Medicine [GZY-ZJ-KJ-23085].