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Endoplasmic reticulum stress contributes to cisplatin-induced chronic kidney disease via the PERK–PKCδ pathway

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Abstract

Background

Cisplatin is an effective chemotherapeutic drug, but it may induce both acute and chronic kidney problems. The pathogenesis of chronic kidney disease (CKD) associated with cisplatin chemotherapy remains largely unclear.

Methods

Mice and renal tubular cells were subjected to repeated low-dose cisplatin (RLDC) treatment to induce CKD and related pathological changes. The roles of endoplasmic reticulum (ER) stress, PERK, and protein kinase C-δ (PKCδ) were determined using pharmacological inhibitors and genetic manipulation.

Results

ER stress was induced by RLDC in kidney tubular cells in both in vivo and in vitro models. ER stress inhibitors given immediately after RLDC attenuated kidney dysfunction, tubular atrophy, kidney fibrosis, and inflammation in mice. In cultured renal proximal tubular cells, inhibitors of ER stress or its signaling kinase PERK also suppressed RLDC-induced fibrotic changes and the expression of inflammatory cytokines. Interestingly, RLDC-induced PKCδ activation, which was blocked by ER stress or PERK inhibitors, suggesting PKCδ may act downstream of PERK. Indeed, suppression of PKCδ with a kinase-dead PKCδ (PKCδ-KD) or Pkcδ-shRNA attenuated RLDC-induced fibrotic and inflammatory changes. Moreover, the expression of active PKCδ-catalytic fragment (PKCδ-CF) diminished the beneficial effects of PERK inhibitor in RLDC-treated cells. Co-immunoprecipitation assay further suggested PERK binding to PKCδ.

Conclusion

These results indicate that ER stress contributes to chronic kidney pathologies following cisplatin chemotherapy via the PERK–PKCδ pathway.

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Data availability

All data supporting the findings during this study are available in this manuscript and supplementary files.

Abbreviations

CKD:

Chronic kidney disease

RLDC:

Repeated low-dose cisplatin

ER:

Endoplasmic reticulum

PKCδ:

Protein kinase C-δ

PKCδ-KD:

Kinase-dead PKCδ

PKCδ-CF:

Active PKCδ-catalytic fragment

AKI:

Acute kidney injury

UPR:

Unfolded protein response

NF-κB:

Nuclear factor-kappa B

FN:

Fibronectin

TUDCA:

Tauroursodeoxycholic acid

4-PBA:

4-Phenylbutyric acid

HE:

Hematoxylin–eosin

BUN:

Blood urea nitrogen

GFR:

Glomerular filtration rate

Mcp-1:

Monocyte chemoattractant protein-1

Cxcl1:

C–X–C motif chemokine ligand 1

W:

Week

M:

Month

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Acknowledgements

The authors would like to thank Huadong Medicine Co., Ltd (Hangzhou, China) for providing technical support of transcutaneous measurement of GFR in this study.

Funding

This study was financially supported by the National Key R&D Program of China [2020YFC2005004] and the National Natural Science Foundation of China [81720108008, 81870474].

Author information

Authors and Affiliations

  1. Hunan Key Laboratory of Kidney Disease and Blood Purification, Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China

    Shaoqun Shu, Hui Wang, Ying Fu, Juan Cai, Anqun Chen, Chengyuan Tang & Zheng Dong

  2. Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China

    Jiefu Zhu

  3. Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA

    Zheng Dong

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  1. Shaoqun Shu
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  2. Hui Wang
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Contributions

ZD, SS, and CT designed the study. SS and HW did most of the experiments. ZD, SS, HW, and CT performed data analysis. All authors contributed to the preparation, writing, and final approval of the manuscript.

Corresponding authors

Correspondence to Chengyuan Tang or Zheng Dong.

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Supplementary Fig. 1 Endoplasmic reticulum (ER) stress is activated in mouse kidneys post-repeated low-dose cisplatin (RLDC) treatment. C57BL/6 male mice were subjected to four weekly injections of cisplatin (8 mg/kg) to collect blood and kidney tissues 1 week (1W) or 1 month (1M) later. FITC-Sinistrin was injected via tail vein before sacrifice to measure glomerular filtration rate (GFR). (a) Diagram of cisplatin treatment. (b) Quantitative analysis of GFR. (c) Concentration of serum creatinine. (d) Concentration of blood urea nitrogen (BUN). (e) Representative HE staining images. Bar= 100 μm. (f) Pathological tubular atrophy score. (g, h) Representative images of Masson trichrome staining and quantitative analysis. Bar= 100 μm. (i, j) Immunoblot analysis of p-PERK, PERK, p-eIF2α, eIF2α, and GAPDH. For quantification, the protein was analyzed through densitometry and then normalized with GAPDH. (k, l) Representative immunohistochemical staining images and quantification of p-PERK expression. Bar= 100 μm. N =6 mice. *p < 0.05; **p < 0.01; ***p < 0.001

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Supplementary Fig. 2 4-PBA and TUDCA inhibit ER stress post-RLDC treatment in kidney tubules. C57BL/6 male mice were subjected to four weekly injections of cisplatin (8 mg/kg). 4-PBA, TUDCA, or saline was given daily after the last injection of cisplatin for 1 week. Kidney tissues were collected 1 month after the last injection of cisplatin. (a–d) Immunoblot analysis of p-PERK, PERK, p-eIF2α, eIF2α, and GAPDH. For quantification, the protein was analyzed through densitometry and then normalized with GAPDH. (e, f) Representative immunohistochemical staining images and quantification of p-PERK expression. Bar= 100 μm. N =6 mice. ***p < 0.001

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Supplementary Fig. 3 ER stress is induced by RLDC treatment in BUMPT cells. BUMPT cells were incubated with different concentrations of cisplatin for 7 hours daily for 4 days. (a) Representative images of phase contrast. Bar= 100 μm. (b-e) Immunoblot analysis of FN, vimentin, p-PERK, PERK, p-eIF2α, eIF2α, and GAPDH. For quantification, the protein was analyzed through densitometry and then normalized with GAPDH. n =4. ***p < 0.001 vs. control

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Supplementary Fig. 4 PKCδ knockdown by Pkcδ-shRNA in BUMPT cells. BUMPT cells were transfected with or without Pkcδ-shRNA. (a–b) Immunoblot analysis of PKCδ and GAPDH. For quantification, the protein was analyzed through densitometry and then normalized with GAPDH. n =4. ***p < 0.001

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Shu, S., Wang, H., Zhu, J. et al. Endoplasmic reticulum stress contributes to cisplatin-induced chronic kidney disease via the PERK–PKCδ pathway. Cell. Mol. Life Sci. 79, 452 (2022). https://doi.org/10.1007/s00018-022-04480-2

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  • DOI: https://doi.org/10.1007/s00018-022-04480-2

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