Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses

Kishi, Seiji; Brooks, Craig R.; Taguchi, Kensei; Ichimura, Takaharu; Mori, Yutaro; Akinfolarin, Akinwande; Gupta, Navin; Galichon, Pierre; Elias, Bertha C.; Suzuki, Tomohisa; Wang, Qian; Gewin, Leslie; Morizane, Ryuji; Bonventre, Joseph V.

doi:10.1172/jci122313

Cited by 84 publications

(78 citation statements)

References 84 publications

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“…Depletion of both ATR and ATM causes marked lethality following irradiation or administration of etoposide compared with the single depletion of ATR or ATM 44 . In addition, a recent study using mice with tubular epithelia specific deletion of ATR demonstrated that cisplatin-induced kidney injury was exacerbated and p53 was upregulated in mutant mice 45 , which is similar to our results of ATM inhibition. Considering these previous observations and our results of paradoxical p53 upregulation by KU55933, defects in ATR or ATM may be compensated by each other and upregulate p53.…”

Section: Discussionsupporting

confidence: 91%

“…First, we found paradoxical upregulation of p53 in cisplatin-and KU55933-treated mouse kidney; however, the mechanism responsible for this upregulation is unclear. Considering the recent report demonstrating the similar upregulation of p53 in tubule-specific ATR knock-out mouse kidney 45 , and the compensatory interaction between ATR and ATM 44 , our results can be partially attributed to the upregulation of ATR, but future experiments are needed. Second, considering the paradoxical upregulation of p53 in cisplatin-and KU55933-treated mouse kidneys, we assumed that p53 was responsible for the exacerbation of kidney injury in our study.…”

Section: Discussionmentioning

confidence: 80%

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Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice

Uehara

Kusaba

Ida

et al. 2020

Sci Rep

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the DnA damage response after kidney injury induces cell cycle arrest in renal tubular epithelial cells, resulting in the secretion of pro-fibrotic cytokines, thereby promoting interstitial fibrosis in a paracrine manner. phosphorylation of ataxia-telangiectasia mutated (AtM) is the initial step in the DNA damage response and subsequent cell cycle arrest; however, the effects of ATM inhibition on the injured kidney have not been explored. Pharmacological ATM inhibition by KU55933 in cisplatin-treated mice did not ameliorate, but instead exacerbated cisplatin-induced DnA damage and tubular injury, thereby increasing mortality. Analysis of isolated tubular epithelia by FACS from bigenic SLC34a1-CreERt2; R26tdTomato proximal tubular-specific reporter mice revealed that KU55933 upregulated p53 and subsequent pro-apoptotic signaling in tubular epithelia of cisplatin-treated mice, leading to marked mitochondrial injury and apoptosis. In addition, KU55933 attenuated several DNA repair processes after cisplatin treatment, including single-strand DnA repair and fanconi anemia pathways, suggesting that DNA repair after dual treatment of cisplatin and KU55933 was not sufficient to prevent the cisplatin-induced tubular injury. our study suggested that AtM inhibition does not increase DnA repair after cisplatin-induced DnA damage and exacerbates tubular injury through the upregulation of p53-dependent pro-apoptotic signaling. Acute kidney injury must be carefully monitored when ATM inhibitors become available in clinical practice in the future. Society is aging worldwide, and the number of patients with end-stage organ failure involving the heart, lung, and kidney, and the costs of treating these diseases are increasing 1. Recent epidemiological investigations demonstrated that a past history of acute kidney injury (AKI) is a strong determinant of the future incidence of CKD 2-4. Maladaptive tubular repair after AKI is one of the underlying mechanisms for this process, eventually leading to tissue fibrosis and the subsequent loss of kidney function 5,6. Numerous insults, such as anticancer drugs and hemodynamic abnormalities, are known causes of AKI 7. Cisplatin is a platinum-based anticancer drug that is widely used to treat many types of cancer, but the main dose-limiting side effect of cisplatin is nephrotoxicity 8,9. Circulating cisplatin is transported into proximal tubular epithelia through the organic cation transporter 2 (OCT2), which is highly expressed in the basolateral membrane 10. The accumulated cisplatin directly binds to DNA, which inhibits transcription and DNA replication, thereby inducing cell death 11,12. For cell survival after injury, complex signaling pathways, known as the DNA damage response (DDR), are activated in the injured cells, and the detection and repair of DNA damage by transient cell cycle arrest are orchestrated to ensure the maintenance of genomic stability or integrity. In DDR, ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR), which are members of the p...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 80%

Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice

Uehara

Kusaba

Ida

et al. 2020

Sci Rep

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“…Renal proximal tubules make up the bulk of the kidney (Kishi et al, 2019;Norman & Fine, 1995), this was visualized in the present study by immunofluorescence staining with the proximal tubulespecific marker, lectin Lotus tetragonolobus agglutinin (LTL) conjugated with fluorescein isothiocyanate (Figure 1b). Early studies F I G U R E 5 Tamoxifen-induced renal proximal tubule-specific reduction of Pik3c3 expression inhibits UNX-induced rpS6 phosphorylation.…”

Section: Discussionmentioning

confidence: 64%

Cre/loxP approach‐mediated downregulation of Pik3c3 inhibits the hypertrophic growth of renal proximal tubule cells

Liu

Yuan

Dai

et al. 2020

Journal Cellular Physiology

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Nephron loss stimulates residual functioning nephrons to undergo compensatory growth. Excessive nephron growth may be a maladaptive response that sets the stage for progressive nephron damage, leading to kidney failure. To date, however, the mechanism of nephron growth remains incompletely understood. Our previous study revealed that class III phosphatidylinositol‐3‐kinase (Pik3c3) is activated in the remaining kidney after unilateral nephrectomy (UNX)‐induced nephron loss, but previous studies failed to generate a Pik3c3 gene knockout animal model. Global Pik3c3 deletion results in embryonic lethality. Given that renal proximal tubule cells make up the bulk of the kidney and undergo the most prominent hypertrophic growth after UNX, in this study we used Cre‐loxP‐based approaches to demonstrate for the first time that tamoxifen‐inducible SLC34a1 promoter‐driven CreERT2 recombinase‐mediated downregulation of Pik3c3 expression in renal proximal tubule cells alone is sufficient to inhibit UNX‐ or amino acid‐induced hypertrophic nephron growth. Furthermore, our mechanistic studies unveiled that the SLC34a1‐CreERT2 recombinase‐mediated Pik3c3 downregulation inhibited UNX‐ or amino acid‐stimulated lysosomal localization and signaling activation of mechanistic target of rapamycin complex 1 (mTORC1) in the renal proximal tubules. Moreover, our additional cell culture experiments using RNAi confirmed that knocking down Pik3c3 expression inhibited amino acid‐stimulated mTORC1 signaling and blunted cellular growth in primary cultures of renal proximal tubule cells. Together, both our in vivo and in vitro experimental results indicate that Pik3c3 is a major mechanistic mediator responsible for sensing amino acid availability and initiating hypertrophic growth of renal proximal tubule cells by activation of the mTORC1–S6K1–rpS6 signaling pathway.

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“…Chronic kidney disease is also associated with inappropriate cell cycle progression in TECs (Yang et al, 2010;Canaud and Bonventre, 2015). The number of tubular cells that undergo G2/M arrest is correlated with the degree of fibrosis (Yang et al, 2010;Kishi et al, 2019). Proximal tubular cells in G2/M arrest activate c-jun NH2-terminal kinase (JNK) signaling and upregulate profibrotic cytokine generation.…”

Section: Cell-cycle Arrest -Defective Repair and Regenerationmentioning

confidence: 99%

New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis

2020

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Epithelial-mesenchymal transition (EMT) is described as the process in which injured renal tubular epithelial cells undergo a phenotype change, acquiring mesenchymal characteristics and morphing into fibroblasts. Initially, it was widely thought of as a critical mechanism of fibrogenesis underlying chronic kidney disease. However, evidence that renal tubular epithelial cells can cross the basement membrane and become fibroblasts in the renal interstitium is rare, leading to debate about the existence of EMT. Recent research has demonstrated that after injury, renal tubular epithelial cells acquire mesenchymal characteristics and the ability to produce a variety of profibrotic factors and cytokines, but remain attached to the basement membrane. On this basis, a new concept of "partial epithelial-mesenchymal transition (pEMT)" was proposed to explain the contribution of renal epithelial cells to renal fibrogenesis. In this review, we discuss the concept of pEMT and the most recent findings related to this process, including cell cycle arrest, metabolic alternation of epithelial cells, infiltration of immune cells, epigenetic regulation as well as the novel signaling pathways that mediate this disturbed epithelial-mesenchymal communication. A deeper understanding of the role and the mechanism of pEMT may help in developing novel therapies to prevent and halt fibrosis in kidney disease.

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Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses

Cited by 84 publications

References 84 publications

Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice

Pharmacological inhibition of ataxia-telangiectasia mutated exacerbates acute kidney injury by activating p53 signaling in mice

Cre/loxP approach‐mediated downregulation of Pik3c3 inhibits the hypertrophic growth of renal proximal tubule cells

New Insights Into the Role and Mechanism of Partial Epithelial-Mesenchymal Transition in Kidney Fibrosis

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