Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney

Sato, Yuki; Mii, Akiko; Hamazaki, Yoko; Fujita, Haruyuki; Nakata, Hirohisa; Masuda, Kyoko; Nishiyama, Shingo; Shibuya, Shinsuke; Haga, Hironori; Ogawa, Osamu; Shimizu, Akira; Narumiya, Shuh; Kaisho, Tsuneyasu; Arita, Makoto; Yanagisawa, Masashi; Miyasaka, Masayuki; Sharma, Kumar; Minato, Nagahiro; Kawamoto, Hiroshi; Yanagita, Motoko

doi:10.1172/jci.insight.87680

Cited by 101 publications

(192 citation statements)

References 54 publications

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“…2 In aged kidneys, in contrast, resident fibroblasts acquire the ability to produce homeostatic chemokines such as CXCL13 and CCL19, attract lymphocytes, and initiate the formation of tertiary lymphoid tissues, causing sustained inflammation and retarding kidney regeneration. 32 The RA-producing ability reported in this article is a new role for the myofibroblasts, which might support the regeneration of injured tubules. Fibroblasts are highly plastic and can acquire various roles in response to their microenvironment, then influence the microenvironment with their newly acquired phenotypes.…”

Section: Discussionmentioning

confidence: 68%

Myofibroblasts acquire retinoic acid–producing ability during fibroblast-to-myofibroblast transition following kidney injury

Nakamura

Sato

Kitai

et al. 2019

Kidney International

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Tubular injury and interstitial fibrosis are the hallmarks of chronic kidney disease. While recent studies have verified that proximal tubular injury triggers interstitial fibrosis, the impact of fibrosis on tubular injury and regeneration remains poorly understood. We generated a novel mouse model expressing diphtheria toxin receptor on renal fibroblasts to allow for the selective disruption of renal fibroblast function. Administration of diphtheria toxin induced upregulation of the tubular injury marker Ngal and caused tubular proliferation in healthy kidneys, whereas administration of diphtheria toxin attenuated tubular regeneration in fibrotic kidneys. Microarray analysis revealed down-regulation of the retinol biosynthesis pathway in diphtheria toxin-treated kidneys. Healthy proximal tubules expressed retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in retinoic acid biosynthesis. After injury, proximal tubules lost RALDH2 expression, whereas renal fibroblasts acquired strong expression of RALDH2 during the transition to myofibroblasts in several models of kidney injury. The retinoic acid receptor (RAR) RARg was expressed in proximal tubules both with and without injury, and aBcrystallin, the product of an RAR target gene, was strongly expressed in proximal tubules after injury. Furthermore, BMS493, an inverse agonist of RARs, significantly attenuated tubular proliferation in vitro. In human biopsy tissue from patients with IgA nephropathy, detection of RALDH2 in the interstitium correlated with older age and lower kidney function. These results suggest a role of retinoic acid signaling and cross-talk between fibroblasts and tubular epithelial cells during tubular injury and regeneration, and may suggest a beneficial effect of fibrosis in the early response to injury.Kidney International (2019) 95, 526-539; https://doi.

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Section: Discussionmentioning

confidence: 68%

Myofibroblasts acquire retinoic acid–producing ability during fibroblast-to-myofibroblast transition following kidney injury

Nakamura

Sato

Kitai

et al. 2019

Kidney International

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“…Mii et al have shown that old mice can develop TLT in the kidneys following IRI, but interestingly young mice lack this capacity (77).…”

Section: Discussionmentioning

confidence: 99%

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Maarouf¹,

Uehara²,

Kasinath³

et al. 2018

JCI Insight

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“…91,[104][105][106] Lymphoid follicle-like structures form within the kidney as tertiary lymphoid tissues in severe AKI to CKD animal models. 107,108 Although B cells and NK cells have been observed in these models, their function in renal inflammation and fibrosis remain poorly understood.…”

Section: Cellsmentioning

confidence: 99%

Renal Inflammation and Fibrosis: A Double-edged Sword

Black

Lever

Agarwal

2019

J Histochem Cytochem.

121

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Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.

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Heterogeneous fibroblasts underlie age-dependent tertiary lymphoid tissues in the kidney

Cited by 101 publications

References 54 publications

Myofibroblasts acquire retinoic acid–producing ability during fibroblast-to-myofibroblast transition following kidney injury

Myofibroblasts acquire retinoic acid–producing ability during fibroblast-to-myofibroblast transition following kidney injury

Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing

Renal Inflammation and Fibrosis: A Double-edged Sword

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