The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis

Magaiver Andrade-Silva; Poonam Dhillon; Andrea Sanchez-Navarro; Dhanunjay Mukhi; Hailong Hu; Lakshmi P Kolligundla; Andrea Bergeson; Amin Abedini; Jonathan Levinsohn; Bernhard Dumoulin; Niels O S Câmara; Jonathan J Miner; Katalin Susztak

doi:10.1016/j.kint.2024.10.021

The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis

Kidney Int. 2024 Nov 19:S0085-2538(24)00788-9. doi: 10.1016/j.kint.2024.10.021. Online ahead of print.

Affiliations

¹ Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil.
² Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
³ Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil.
⁴ Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁵ Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Penn/CHOP Kidney Innovation Center, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA. Electronic address: [email protected].

PMID: 39566842
DOI: 10.1016/j.kint.2024.10.021

Abstract

Endoplasmic reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.

Keywords: PERK; chronic kidney disease; kidney fibrosis; nucleotide sensors; unfolded protein response.