Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney

Kumar, Sanjeev; Liu, Jing; Pang, Paul; Krautzberger, A. Michaela; Reginensi, Antoine; Akiyama, Haruhiko; Schedl, Andreas; Humphreys, Benjamin D.; McMahon, Andrew P.

doi:10.1016/j.celrep.2015.07.034

Cited by 192 publications

(225 citation statements)

References 55 publications

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“…A characteristic of successful repair is the subsequent downregulation of Kim-1 during redifferentiation, along with other dedifferentiation markers, such as Pax2, and EMT markers Vimentin and Snail1 [6]. The Sry-box family transcription factor, Sox9, is also induced during injury [7]. Similar to Kim-1, expression of Sox9 is low in uninjured kidneys, and shows a dramatic upregulation 24 hours after ischemia reperfusion injury (IRI) in murine models [7].…”

Section: Tubular Injury and Repairmentioning

confidence: 99%

“…The Sry-box family transcription factor, Sox9, is also induced during injury [7]. Similar to Kim-1, expression of Sox9 is low in uninjured kidneys, and shows a dramatic upregulation 24 hours after ischemia reperfusion injury (IRI) in murine models [7]. These Sox9+ injured PT cells are actively proliferating, with half of Sox9+ cells co-expressing Kim-1 [7].…”

Section: Tubular Injury and Repairmentioning

confidence: 99%

“…Similar to Kim-1, expression of Sox9 is low in uninjured kidneys, and shows a dramatic upregulation 24 hours after ischemia reperfusion injury (IRI) in murine models [7]. These Sox9+ injured PT cells are actively proliferating, with half of Sox9+ cells co-expressing Kim-1 [7]. Indeed, Kang et al showed that Sox9+ cells contributed to repair of proximal, distal and loop of Henle segments after folic acid injury and IRI [8].…”

Section: Tubular Injury and Repairmentioning

confidence: 99%

“…Indeed, Kang et al showed that Sox9+ cells contributed to repair of proximal, distal and loop of Henle segments after folic acid injury and IRI [8]. Using the Sox9 driven Cre-ER 2 model crossed with R26R-tdTomato, Kumar et al showed that PT cells that initiated de novo expression of Sox9 after injury, contributed the most to repair, further implicating dedifferentiation as the predominant mechanism of epithelial repair [7]. Additionally, both PT-specific deletion of Sox9 in repair, and global deletion of Kim-1 during injury, exacerbated injury and delayed repair [7–9].…”

Section: Tubular Injury and Repairmentioning

confidence: 99%

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Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

hAinmhire

Humphreys²

2017

Nephron

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End-stage renal disease (ESRD) is common, costly, and it results from progressive chronic kidney disease (CKD). ESRD claims many lives every year. It is increasingly recognized that episodes of acute kidney injury (AKI) predispose to the future development of CKD and ESRD. While our understanding of the pathophysiology of the AKI to CKD transition is improving, there are no validated therapeutic strategies to prevent this transition. In this review, we summarize the recent progress made in defining the cellular and molecular events underlying the AKI to CKD transition and highlight potential therapeutic targets and strategies to reduce the incidence of CKD following AKI.

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Section: Tubular Injury and Repairmentioning

confidence: 99%

Section: Tubular Injury and Repairmentioning

confidence: 99%

Section: Tubular Injury and Repairmentioning

confidence: 99%

Section: Tubular Injury and Repairmentioning

confidence: 99%

See 2 more Smart Citations

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

hAinmhire

Humphreys²

2017

Nephron

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“…Other than an implantation of isolated stem cells, research is following up with a biomedical activation of quiescent stem cells occurring in adult renal parenchyma [14-17]. An alternative approach is to investigate reactivation of earlier stem cell niches represented during entire organ development of the original source of renal parenchyma [18, 19].…”

mentioning

confidence: 99%

Reading First Coordinates from the Nephrogenic Zone in Human Fetal Kidney

Minuth¹

2017

Nephron

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While substantial information is available on organ anlage and the primary formation of nephrons, molecular mechanisms acting during the late development of the human kidney have received an astonishing lack of attention. In healthy newborn babies, nephrogenesis takes place unnoticed until birth. Upon delivery, morphogenetic activity in the nephrogenic zone decreases, and the stem cell niches aligned beyond the organ capsule vanish by an unknown signal. However, this signal also plays a key role in preterm and low birth weight babies. Although they are born in a phase of active nephrogenesis, pathological findings illustrate that they evolve to a high incidence oligonephropathy and prematurity of renal parenchyma. Different extra- and intrauterine influences seem to be responsible, but independent from chemical nature, all of them culminate in the nephrogenic zone. One assumes that the marred development is caused either by an overshoot of metabolites, misleading signaling of morphogens, unbalanced synthesis of extracellular matrix or restricted contact between mesenchymal and epithelial stem cells. Even more surprising is that there is only a few vague morphological information of the nephrogenic zone in the human fetal kidney available and ultrastructural data is severely lacking. On this account, the first coordinates were determined by optical microscopy and morphometry. Without claiming to be complete, generated results made it possible to create schematic illustrations true to scale for orientation. It will help graduating students, young pediatricians, pathologists, and scientists working in the field of biomedicine to interpret professionally the nephrogenic zone and contained niches.

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Nuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanoma

Seefried

Haller

Fukuda

et al. 2022

Intl Journal of Cancer

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AMPHIREGULIN (AREG) is a multifaceted molecule, which acts not only as an extracellular ligand for EGF receptor (EGFR), but also as an intracellular signaling molecule. It remains elusive, however, whether AREG has a tumor suppressive or oncogenic role in melanoma. Here, we found that several melanoma cell lines express AREG, but the expression does not correlate with that of EGFR. Recombinant AREG and the neutralizing antibody experiments showed that intracellular AREG plays an important role in melanoma, implying a divergent function of AREG in addition to the role as a ligand for EGFR. Further investigation of this mechanism revealed that particularly nuclear‐localized AREG regulates IGF‐1R, P21 (Cip1/Waf1), TP53 and JARID1B protein accumulation in the nucleus. Furthermore, manipulation of nuclear AREG levels has influence on heterochromatin condensation (HP1beta, SETDB1) and trimethylation of histones H3K9 and H3K4. As these molecules correspond to previously identified markers for slow‐cycling drug resistant cells, we speculate that nuclear AREG predisposes cells to resistance to therapy. According to the hypothesis, we detected the accumulation of AREG in the nucleus of SK‐Mel‐28‐VR, which was cultured under Vemurafenib (VR) selection pressure, and this correlates with JARID1B expression. Here, knockdown of AREG makes the previously resistant cells more sensitive to VR treatment, resulting in inhibited proliferation. Taken together, we suggest that nuclear AREG affects a slow‐cycling phenotype and increases resistance to VR, raising a possibility that AREG might be a potential therapeutic target for resistance in melanoma.

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Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney

Cited by 192 publications

References 55 publications

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

Reading First Coordinates from the Nephrogenic Zone in Human Fetal Kidney

Nuclear AREG affects a low‐proliferative phenotype and contributes to drug resistance of melanoma

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