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Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease

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Abstract

Kidney disease is the 6th fastest-growing cause of death and a serious global health concern that urges effective therapeutic options. The inflammatory response is an initial reaction from immune and parenchymal cells in kidney diseases. Toll-like receptors (TLR) 2 and 4 are highly expressed by various kidney cells and respond to ‘signaling danger’ proteins, such as high mobility group box binding protein 1 (HMGB1) and prompt the progression of kidney disease by releasing inflammatory mediators. Burgeoning reports suggest that both SGLT2 and ER stress elevates TLR2/4 signaling via different axis. Moreover, SGLT2 signaling aggravates inflammation under the disease condition by promoting the NLR family pyrin domain-containing three inflammasomes and ER stress. Intriguingly, TLR2/4 downstream adaptors activate ER stress regulators. The above-discussed interactions imply that TLR2/4 does more than immune response during kidney disease. Here, we discuss in detail evidence of the roles and regulation of TLR2/4 in the context of a relationship between ER stress and SGLT2. Also, we highlighted different preclinical studies of SGLT2 inhibitors against TLR2/4 signaling in various kidney diseases. Moreover, we discuss the observational and interventional evidence about the relation between TLR2/4, ER stress, and SGLT2, which may represent the TLR2/4 as a potential therapeutic target for kidney disease.

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Acknowledgements

ABG sincerely acknowledges the financial support provided by the Birla Institute of Technology and Science, Pilani, Pilani Campus, for carrying out this work. HJA was supported by the Deutsche Forschungsgemeinschaft (AN372/14-4 and 30-1).

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Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, 333031, India

    Vishwadeep Shelke, Ajinath Kale & Anil Bhanudas Gaikwad

  2. Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, 80336, Munich, Germany

    Hans-Joachim Anders

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  1. Vishwadeep Shelke
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  2. Ajinath Kale
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  3. Hans-Joachim Anders
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  4. Anil Bhanudas Gaikwad
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VS: Literature research, Writing—Original draft preparation, Review. AK: Writing—Review & Editing. H-JA: Participated in designing the manuscript, edited, and prepared it for submission. ABG: Conceptualization, Supervision.

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Correspondence to Anil Bhanudas Gaikwad.

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Shelke, V., Kale, A., Anders, HJ. et al. Toll-like receptors 2 and 4 stress signaling and sodium-glucose cotransporter-2 in kidney disease. Mol Cell Biochem 478, 1987–1998 (2023). https://doi.org/10.1007/s11010-022-04652-5

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