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The injury-induced transcription factor SOX9 alters the expression of LBR, HMGA2, and HIPK3 in the human kidney

Kha, Michelle ; Krawczyk, Krzysztof LU orcid ; Choong, Oi Kuan ; De Luca, Francesco ; Altiparmak, Gulay ; Kallberg, Eva LU ; Nilsson, Helen LU ; Leandersson, Karin LU orcid ; Sward, Karl LU and Johansson, Martin E. (2023) In American Journal of Physiology - Renal Physiology 324(1). p.75-90
Abstract

Induction of SRY box transcription factor 9 (SOX9) has been shown to occur in response to kidney injury in rodents, where SOX9-positive cells proliferate and regenerate the proximal tubules of injured kidneys. Additionally, SOX9-positive cells demonstrate a capacity to differentiate toward other nephron segments. Here, we characterized the role of SOX9 in normal and injured human kidneys. SOX9 expression was found to colocalize with a proportion of so-called scattered tubular cells in the uninjured kidney, a cell population previously shown to be involved in kidney injury and regeneration. Following injury and in areas adjacent to inflammatory cell infiltrates, SOX9-positive cells were increased in number. With the use of primary... (More)

Induction of SRY box transcription factor 9 (SOX9) has been shown to occur in response to kidney injury in rodents, where SOX9-positive cells proliferate and regenerate the proximal tubules of injured kidneys. Additionally, SOX9-positive cells demonstrate a capacity to differentiate toward other nephron segments. Here, we characterized the role of SOX9 in normal and injured human kidneys. SOX9 expression was found to colocalize with a proportion of so-called scattered tubular cells in the uninjured kidney, a cell population previously shown to be involved in kidney injury and regeneration. Following injury and in areas adjacent to inflammatory cell infiltrates, SOX9-positive cells were increased in number. With the use of primary tubular epithelial cells (PTECs) obtained from human kidney tissue, SOX9 expression was spontaneously induced in culture and further increased by transforming growth factor-b1, whereas it was suppressed by interferon-c. siRNA-mediated knockdown of SOX9 in PTECs followed by analysis of differential gene expression, immunohistochemical expression, and luciferase promoter assays suggested lamin B receptor (LBR), high mobility group AT-hook 2 (HMGA2), and homeodomain interacting protein kinase 3 (HIPK3) as possible target genes of SOX9. Moreover, a kidney explant model was used to demonstrate that only SOX9-positive cells survive the massive injury associated with kidney ischemia and that the surviving SOX9-positive cells spread and repopulate the tubules. Using a wound healing assay, we also showed that SOX9 positively regulated the migratory capacity of PTECs. These findings shed light on the functional and regulatory aspects of SOX9 activation in the human kidney during injury and regeneration.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
kidney injury, regeneration, SRY box transcription factor 9
in
American Journal of Physiology - Renal Physiology
volume
324
issue
1
pages
75 - 90
publisher
American Physiological Society
external identifiers
  • pmid:36454702
  • scopus:85144588898
ISSN
1931-857X
DOI
10.1152/ajprenal.00196.2022
language
English
LU publication?
yes
id
b295265c-5d16-4cf6-afcc-104b1a1aeb8a
date added to LUP
2023-02-07 15:18:26
date last changed
2024-04-04 16:25:02
@article{b295265c-5d16-4cf6-afcc-104b1a1aeb8a,
  abstract     = {{<p>Induction of SRY box transcription factor 9 (SOX9) has been shown to occur in response to kidney injury in rodents, where SOX9-positive cells proliferate and regenerate the proximal tubules of injured kidneys. Additionally, SOX9-positive cells demonstrate a capacity to differentiate toward other nephron segments. Here, we characterized the role of SOX9 in normal and injured human kidneys. SOX9 expression was found to colocalize with a proportion of so-called scattered tubular cells in the uninjured kidney, a cell population previously shown to be involved in kidney injury and regeneration. Following injury and in areas adjacent to inflammatory cell infiltrates, SOX9-positive cells were increased in number. With the use of primary tubular epithelial cells (PTECs) obtained from human kidney tissue, SOX9 expression was spontaneously induced in culture and further increased by transforming growth factor-b1, whereas it was suppressed by interferon-c. siRNA-mediated knockdown of SOX9 in PTECs followed by analysis of differential gene expression, immunohistochemical expression, and luciferase promoter assays suggested lamin B receptor (LBR), high mobility group AT-hook 2 (HMGA2), and homeodomain interacting protein kinase 3 (HIPK3) as possible target genes of SOX9. Moreover, a kidney explant model was used to demonstrate that only SOX9-positive cells survive the massive injury associated with kidney ischemia and that the surviving SOX9-positive cells spread and repopulate the tubules. Using a wound healing assay, we also showed that SOX9 positively regulated the migratory capacity of PTECs. These findings shed light on the functional and regulatory aspects of SOX9 activation in the human kidney during injury and regeneration.</p>}},
  author       = {{Kha, Michelle and Krawczyk, Krzysztof and Choong, Oi Kuan and De Luca, Francesco and Altiparmak, Gulay and Kallberg, Eva and Nilsson, Helen and Leandersson, Karin and Sward, Karl and Johansson, Martin E.}},
  issn         = {{1931-857X}},
  keywords     = {{kidney injury; regeneration; SRY box transcription factor 9}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{75--90}},
  publisher    = {{American Physiological Society}},
  series       = {{American Journal of Physiology - Renal Physiology}},
  title        = {{The injury-induced transcription factor SOX9 alters the expression of LBR, HMGA2, and HIPK3 in the human kidney}},
  url          = {{http://dx.doi.org/10.1152/ajprenal.00196.2022}},
  doi          = {{10.1152/ajprenal.00196.2022}},
  volume       = {{324}},
  year         = {{2023}},
}