Kidney Regeneration: Lessons from Development

Chiba, Takuto; Hukriede, Neil A.; Caestecker, Mark P. de

doi:10.1007/s40139-015-0069-z

Cited by 10 publications

(7 citation statements)

References 124 publications

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“…At that time point, no appreciable tubular injury and inflammatory infiltration is evident (Fig. 1), consistent with the timeline established previously for tubular damage, endothelial impairment, and peritubular inflammation in this model (41–43). These results indicate that fibroblast activation, as defined by vimentin expression, is the earliest cellular event documented in AKI thus far.…”

Section: Discussionsupporting

confidence: 90%

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Zhou

Liu

et al. 2019

The FASEB Journal

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Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality. AKI is characterized by tubular injury, inflammation, and vascular impairment. However, the role of interstitial fibroblasts in the pathogenesis of AKI is largely unknown. Here, we show that fibroblasts were activated, as defined by vimentin expression, at 1 h after AKI triggered by ischemia‐reperfusion injury (IRI). They rapidly entered the cell cycle with Ki‐67‐positive staining, which started at 1 h and peaked at 12 h after IRI, whereas tubular cell proliferation peaked at 3 d. The trigger for such an early activation of fibroblasts was identified as sonic hedgehog (Shh), which was rapidly induced in renal tubules and could target interstitial fibroblasts. Tubule‐specific knockout of Shh in mice inhibited fibroblast activation and aggravated kidney injury and functional decline after IRI. Likewise, pharmacologic inhibition of Shh signaling with cyclopamine also hindered fibroblast activation and exacerbated kidney damage. These studies uncover that tubule‐derived Shh triggers the early activation of fibroblasts, which is required for kidney repair and regeneration. Our findings for the first time illustrate a previously unrecognized importance of interstitial fibroblasts in conferring renal protection in AKI.—Zhou, D., Fu, H., Liu, S., Zhang L., Xiao, L., Bastacky, S. I., Liu, Y. Early activation of fibroblasts is required for kidney repair and regeneration after injury. FASEB J. 33, 12576–12587 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 90%

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Zhou

Liu

et al. 2019

The FASEB Journal

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“…Both innate and adaptive immune mechanisms are important mediators of kidney injury and repair, and several different types of immune cells participate in these processes [ 1 – 3 ]. Resident mononuclear phagocytic cells (MPCs) in kidney serve sentinel roles in protection against pathogens and maintenance of homeostatic microenvironment [ 4 , 5 ]. MPCs are functionally classified as either macrophages by their phagocytic role or as dendritic cells (DCs) by their antigen-presenting phenotype [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of kidney CD45intCD11bintF4/80+MHCII+CX3CR1+Ly6C- “intermediate mononuclear phagocytic cells”

et al. 2018

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Kidney immune cells play important roles in pathogenesis of many diseases, including ischemia-reperfusion injury (IRI) and transplant rejection. While studying murine kidney T cells, we serendipitously identified a kidney mononuclear phagocytic cell (MPC) subset characterized by intermediate surface expression of CD45 and CD11b. These CD45intCD11bint MPCs were further identified as F4/80+MHCII+CX3CR1+Ly6C- cells, comprising ~17% of total CD45+ cells in normal mouse kidney (P < 0.01) and virtually absent from all other organs examined except the heart. Systemic clodronate treatment had more significant depletive effect on the CD45intCD11bint population (77.3%±5.9%, P = 0.03) than on CD45highCD11b+ population (14.8%±16.6%, P = 0.49). In addition, CD45intCD11bint MPCs had higher phagocytic function in the normal kidney (35.6%±3.3% vs. 24.1%±2.2%, P = 0.04), but lower phagocytic capacity in post-ischemic kidney (54.9%±1.0% vs. 67.8%±1.9%, P < 0.01) compared to the CD45highCD11b+ population. Moreover, the CD45intCD11bint population had higher intracellular production of the pro-inflammatory tumor necrosis factor (TNF)-α (58.4%±5.2% vs. 27.3%±0.9%, P < 0.001) after lipopolysaccharide (LPS) stimulation and lower production of the anti-inflammatory interleukin (IL)-10 (7.2%±1.3% vs. 14.9%±2.2%, P = 0.02) following kidney IRI, suggesting a functional role under inflammatory conditions. The CD45intCD11bint cells increased early after IRI, and then abruptly decreased 48h later, whereas CD45highCD11b+ cells steadily increased after IRI before declining at 72h (P = 0.03). We also identified the CD45intCD11bint MPC subtype in human kidney. We conclude that CD45intCD11bint F4/80+MHCII+CX3CR1+Ly6C-population represent a unique subset of MPCs found in both mouse and human kidneys. Future studies will further characterize their role in kidney health and disease.

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“…This would suggest that the roles of such genes in response to injury are distinct from their roles in development. 98,99 Some of these unexpected changes may reflect the restriction of this analysis to a single early time point, however, overall this paints quite a different picture of the response process. What had been assumed to be the return of epithelial cell types to a progenitor state followed by the recapitulation of normal morphogenetic programs is more likely to represent the independent activation of similar gene pathways for a distinct role.…”

Section: Recent Transcriptional Analysis Of Kidney Repair: Does This mentioning

confidence: 97%

Does Renal Repair Recapitulate Kidney Development?

Little

Kairath

2016

JASN

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Over a decade ago, it was proposed that the regulation of tubular repair in the kidney might involve the recapitulation of developmental pathways. Although the kidney cannot generate new nephrons after birth, suggesting a low level of regenerative competence, the tubular epithelial cells of the nephrons can proliferate to repair the damage after AKI. However, the debate continues over whether this repair involves a persistent progenitor population or any mature epithelial cell remaining after injury. Recent reports have highlighted the expression of Sox9, a transcription factor critical for normal kidney development, during postnatal epithelial repair in the kidney. Indeed, the proliferative response of the epithelium involves expression of several pathways previously described as being involved in kidney development. In some instances, these pathways are also apparently involved in the maladaptive responses observed after repeated injury. Whether development and repair in the kidney are the same processes or we are misinterpreting the similar expression of genes under different circumstances remains unknown. Here, we review the evidence for this link, concluding that such parallels in expression may more correctly represent the use of the same pathways in a distinct context, likely triggered by similar stressors.

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Kidney Regeneration: Lessons from Development

Cited by 10 publications

References 124 publications

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Characterization of kidney CD45intCD11bintF4/80+MHCII+CX3CR1+Ly6C- “intermediate mononuclear phagocytic cells”

Does Renal Repair Recapitulate Kidney Development?

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