2. Academic Validation
  3. Blockage of Akt activation suppresses cadmium-induced renal tubular cellular damages through aggrephagy in HK-2 cells

Blockage of Akt activation suppresses cadmium-induced renal tubular cellular damages through aggrephagy in HK-2 cells

  • Sci Rep. 2024 Jun 24;14(1):14552. doi: 10.1038/s41598-024-64579-3.
Kota Fujiki 1,  K Tanabe 2,  S Suzuki 3,  A Mochizuki 4,  M Mochizuki-Kashio 5,  T Sugaya 6,  T Mizoguchi 3,  M Itoh 3,  A Nakamura-Ishizu 5,  H Inamura 7,  M Matsuoka 7
Affiliations

Affiliations

  • 1 Department of Hygiene and Public Health, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. bunnsidairoku@gmail.com.
  • 2 Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
  • 3 Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
  • 4 Department of Bio-Medical Engineering, School of Engineering, Tokai University, Kanagawa, 259-1143, Japan.
  • 5 Department of Microanatomy and Development Biology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
  • 6 Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Kanagawa, 216-8511, Japan.
  • 7 Department of Hygiene and Public Health, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
PMID: 38914593 DOI: 10.1038/s41598-024-64579-3
Abstract

We have reported that an environmental pollutant, cadmium, promotes cell death in the human renal tubular cells (RTCs) through hyperactivation of a serine/threonine kinase Akt. However, the molecular mechanisms downstream of Akt in this process have not been elucidated. Cadmium has a potential to accumulate misfolded proteins, and proteotoxicity is involved in cadmium toxicity. To clear the roles of Akt in cadmium exposure-induced RTCs death, we investigated the possibility that Akt could regulate proteotoxicity through Autophagy in cadmium chloride (CdCl2)-exposed HK-2 human renal proximal tubular cells. CdCl2 exposure promoted the accumulation of misfolded or damaged proteins, the formation of aggresomes (pericentriolar cytoplasmic inclusions), and aggrephagy (selective Autophagy to degrade aggresome). Pharmacological inhibition of Akt using MK2206 or Akti-1/2 enhanced aggrephagy by promoting dephosphorylation and nuclear translocation of transcription factor EB (TFEB)/transcription factor E3 (TFE3), lysosomal transcription factors. TFEB or TFE3 knockdown by siRNAs attenuated the protective effects of MK2206 against cadmium toxicity. These results suggested that aberrant activation of Akt attenuates aggrephagy via TFEB or TFE3 to facilitate CdCl2-induced cell death. Furthermore, these roles of Akt/TFEB/TFE3 were conserved in CdCl2-exposed primary human RTCs. The present study shows the molecular mechanisms underlying Akt activation that promotes cadmium-induced RTCs death.

Keywords

Aggresome; Akt; Cadmium; Cell death; Renal proximal tubular cells.

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