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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

ABSTRACT: Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residual kidney function early during AKI. This survival mechanism comes at the cost of senescence of polyploid TC promoting interstitial fibrosis and CKD in AKI survivors. However, targeting TC polyploidization after the early AKI phase can prevent AKI-CKD transition without influencing AKI lethality. Senolytic treatment prevents CKD by blocking repeated TC polyploidization cycles. These results revise the current pathophysiological concept of how the kidney responds to acute injury and identify a novel druggable target to improve prognosis in AKI survivors.

SUBMITTER: De Chiara L

PROVIDER: S-EPMC9532438 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

De Chiara Letizia L Conte Carolina C Semeraro Roberto R Diaz-Bulnes Paula P Angelotti Maria Lucia ML Mazzinghi Benedetta B Molli Alice A Antonelli Giulia G Landini Samuela S Melica Maria Elena ME Peired Anna Julie AJ Maggi Laura L Donati Marta M La Regina Gilda G Allinovi Marco M Ravaglia Fiammetta F Guasti Daniele D Bani Daniele D Cirillo Luigi L Becherucci Francesca F Guzzi Francesco F Magi Alberto A Annunziato Francesco F Lasagni Laura L Anders Hans-Joachim HJ Lazzeri Elena E Romagnani Paola P

Nature communications 20221004 1

Acute kidney injury (AKI) is frequent, often fatal and, for lack of specific therapies, can leave survivors with chronic kidney disease (CKD). We characterize the distribution of tubular cells (TC) undergoing polyploidy along AKI by DNA content analysis and single cell RNA-sequencing. Furthermore, we study the functional roles of polyploidization using transgenic models and drug interventions. We identify YAP1-driven TC polyploidization outside the site of injury as a rapid way to sustain residu ...[more]

PMID: 36195583

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Project description:BackgroundInterleukin-17C (IL-17C), a member of the IL-17 cytokine family, plays a pathogenic role in kidney diseases. Our previous studies have shown that pre-administration of IL-17C neutralizing antibody attenuated acute kidney injury (AKI, a common acute inflammation associated renal disease). In this study, we explored whether post-ischemia reperfusion (IR) of IL-17C blockade has therapeutic effects on AKI and whether IL-17C is involved in the pathogenesis of diabetic nephropathy (DN), a major type of chronic inflammation-associated kidney disease.Methods12-week-old male C57BL/6JGpt mice were treated with IL-17C neutralizing antibody or normal IgG control antibody at 3 h after reperfusion. Renal injury, inflammation, and oxidative stress were assessed. Additionally, we examined renal IL-17C expression in patients with DN and db/db mice and evaluated albuminuria, mesangial matrix accumulation and podocyte loss in db/db mice with IL-17C neutralization. Knockdown of NF-κB p65 using siRNA, and blocking Hypoxia-inducible factor-1α (HIF-1α) using YC-1 in mice and HIF-1α Decoy in HK2 cells were investigated to explore the possible signaling pathway involved in IL-17C regulation.FindingsWe found that delayed IL-17C neutralization had similar reno-protective effects on renal ischemia-reperfusion injury (IRI). Additionally, renal IL-17C expression was increased in patients with DN and db/db mice, while IL-17C blockade significantly attenuated DN, accompanied with blunted albuminuria, mesangial matrix accumulation, and podocyte loss. Moreover, IL-17C neutralization significantly repressed the expression of downstream pro-inflammatory cytokines, inflammatory cell infiltration, and Th17/IL-17A activation both in mice with renal IRI and DN. Mechanistical studies demonstrated that hypoxia or high glucose-induced IL-17C up-regulation was predominantly mediated by NF-κB pathway.InterpretationIL-17C participates in the pathogenesis of AKI and DN and inhibition of IL-17C shows potential as a therapeutic strategy for AKI and DN.FundingThe National Natural Science Foundation of China (81770741, 81700601 and 81870504).

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Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

Publications

Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease.

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