Deactivation of the Unfolded Protein Response Aggravated Renal AA Amyloidosis in HSF1 Deficiency Mice

Abstract

Systemic amyloid A (AA) amyloidosis, which is considered the second most common form of systemic amyloidosis usually takes place several years prior to the occurrence of chronic inflammation, generally involving the kidney. Activated HSF1, which alleviated unfolded protein response (UPR) or enhanced HSR, is the potential therapeutic target of many diseases. However, the effect of HSF1 on AA amyloidosis remains unclear. This study focused on evaluating effect of HSF1 on AA amyloidosis based on HSF1 knockout mice. As a result, aggravated amyloid deposits and renal dysfunction have been found in HSF1 knockout mice. In progressive AA amyloidosis, HSF1 deficiency enhances serum amyloid A production might to lead to severe AA amyloid deposition in mice, which may be related to deactivated unfolded protein response as well as enhanced inflammation. Thus, HSF1 plays a significant role on UPR related pathway impacting AA amyloid deposition, which can mitigate amyloidogenic proteins from aggregation pathologically and is the possible way for intervening with the pathology of systemic amyloid disorder. In conclusion, HSF1 could not only serve as a new target for AA amyloidosis treatment in the future, but HSF1 knockout mice also can be considered as a valuable novel animal model for renal AA amyloidosis.

Keywords:

• AA amyloidosis
• HSF1 deficiency
• mice model
• unfolded protein response
• microarray

Acknowledgments

We thank Ms Xiaojun Wang and Ms Jianmei Yue (Division of Laboratory Animal Research, Hebei Medical University) for animal care.

Authors contributions

JQ designed the study. SX made major contributions to experiments and data acquisition. XL and LB were responsible for mouse breeding and performing some experiments. WL, FY and JQ analyzed the data. JQ, JH and YS helped perform some experiments. WL and FY discussed and wrote the manuscript. JQ was in charge of project supervision. All authors were involved in drafting and revising the manuscript.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

The data that support the findings of this study are openly available in figshare at http://doi.org/10.6084/m9.figshare.24082599.

Ethics approval

All animal experiments were carried out according to the ethical policies and the procedures approved by the Division of Laboratory Animal Research, Hebei Medical University (IACC-Hebmu-2021036).

Additional information

Funding

The work was supported by the Natural Science Foundation of China in Hebei Province (Grant numbers H2020206399, H2020206340); the National Natural Science Foundation of China (Grant number 81770720); Scientific Research Foundation for Returned Scholars of Hebei Province of China (Grant number C20210352); Research Foundation of Hebei Provincial Health Commission (Grant number 20220128), Medical research Foundation of Health Department of Hebei Province (Grant number 20231088).