Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury
Abstract Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex v...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07386-6 |
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| author | Kurt T. K. Giuliani Purba Nag Benjamin C. Adams Xiangju Wang Seokchan Hong Anca Grivei Rebecca L. Johnston Nicola Waddell Kenneth K. C. Ho Yilin Tian Muhammad Ali Khan Chang Seong Kim Monica S. Y. Ng Glenda Gobe Jacobus P. J. Ungerer Josephine M. Forbes Helen G. Healy Andrew J. Kassianos |
| author_facet | Kurt T. K. Giuliani Purba Nag Benjamin C. Adams Xiangju Wang Seokchan Hong Anca Grivei Rebecca L. Johnston Nicola Waddell Kenneth K. C. Ho Yilin Tian Muhammad Ali Khan Chang Seong Kim Monica S. Y. Ng Glenda Gobe Jacobus P. J. Ungerer Josephine M. Forbes Helen G. Healy Andrew J. Kassianos |
| author_sort | Kurt T. K. Giuliani |
| collection | DOAJ |
| description | Abstract Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, increased p21 expression, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a type I IL-1 receptor (IL-1RI) neutralizing antibody or a senolytic drug combination, quercetin+dasatinib, attenuated senescent cell burden. In vitro findings were validated in human CKD bio-specimens (kidney tissue, urine), with elevated PTEC IL-1RI expression and senescence (SA-β-gal activity) detected in fibrotic kidneys and numbers of senescent (SA-β-gal+) urinary PTECs correlating with urinary IL-1β levels and severity of interstitial fibrosis. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD. |
| format | Article |
| id | doaj-art-6d7db26e00ce4c0d8780988853b66443 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-6d7db26e00ce4c0d8780988853b664432025-02-02T12:44:52ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111210.1038/s41419-025-07386-6Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injuryKurt T. K. Giuliani0Purba Nag1Benjamin C. Adams2Xiangju Wang3Seokchan Hong4Anca Grivei5Rebecca L. Johnston6Nicola Waddell7Kenneth K. C. Ho8Yilin Tian9Muhammad Ali Khan10Chang Seong Kim11Monica S. Y. Ng12Glenda Gobe13Jacobus P. J. Ungerer14Josephine M. Forbes15Helen G. Healy16Andrew J. Kassianos17Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandQIMR Berghofer Medical Research InstituteFaculty of Medicine, University of QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandFaculty of Medicine, University of QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandFaculty of Medicine, University of QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandConjoint Internal Medicine Laboratory, Chemical Pathology, Pathology QueenslandAbstract Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O2) or hypoxic (1% O2) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 ‘unique’ differentially expressed genes (DEGs) compared to normoxic PTECs, with ‘cell cycle’ the most significantly enriched KEGG pathway based on ‘unique’ down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, increased p21 expression, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a type I IL-1 receptor (IL-1RI) neutralizing antibody or a senolytic drug combination, quercetin+dasatinib, attenuated senescent cell burden. In vitro findings were validated in human CKD bio-specimens (kidney tissue, urine), with elevated PTEC IL-1RI expression and senescence (SA-β-gal activity) detected in fibrotic kidneys and numbers of senescent (SA-β-gal+) urinary PTECs correlating with urinary IL-1β levels and severity of interstitial fibrosis. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.https://doi.org/10.1038/s41419-025-07386-6 |
| spellingShingle | Kurt T. K. Giuliani Purba Nag Benjamin C. Adams Xiangju Wang Seokchan Hong Anca Grivei Rebecca L. Johnston Nicola Waddell Kenneth K. C. Ho Yilin Tian Muhammad Ali Khan Chang Seong Kim Monica S. Y. Ng Glenda Gobe Jacobus P. J. Ungerer Josephine M. Forbes Helen G. Healy Andrew J. Kassianos Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury Cell Death and Disease |
| title | Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury |
| title_full | Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury |
| title_fullStr | Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury |
| title_full_unstemmed | Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury |
| title_short | Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury |
| title_sort | human proximal tubular epithelial cell interleukin 1 receptor signalling triggers g2 m arrest and cellular senescence during hypoxic kidney injury |
| url | https://doi.org/10.1038/s41419-025-07386-6 |
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