Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors

Kaneko, Keiichi; Sato, Yuki; Uchino, Eiichiro; Toriu, Naoya; Shigeta, Mayo; Kanazawa, Hiroshi; Endo, Shuichiro; Fukuma, Shingo; Yanagita, Motoko

doi:10.1016/j.kint.2022.04.026

Cited by 17 publications

(7 citation statements)

References 33 publications

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“…When exposed to hypoxia, renin‐producing JG cells are converted to EPO‐producing cells (Broeker, Fuchs, et al., 2022; Kurt et al., 2013). Conversely, in rodent and human cases of pronounced interstitial fibrosis, myofibroblasts, which have lost their ability to synthetize EPO (Asada et al., 2011; Kaneko et al., 2022), start to produce renin (Miyauchi et al., 2021). This cell switch correlates with the increase in systemic blood pressure observed in patients suffering from chronic tubulointerstitial nephritis (Miyauchi et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Induced pluripotent stem cell (iPS) technology offers new opportunities for both mechanistic studies and development of stem cell‐based therapies. Although it could be very challenging to revert renin‐producing myofibroblasts (Miyauchi et al., 2021) into EPO‐producing fibroblasts (Kaneko et al., 2022), one can envision stem cell‐based therapies using EPO‐producing cells from patient‐derived iPS cells. The conversion of iPS cells to NCCs has already been established (Chambers et al., 2009) and iPS generated from P0‐Cre transgene already exist (Ogawa et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Amongst them, renin is a key regulator of blood pressure and fluid–electrolyte homeostasis, whereas erythropoietin (EPO) controls oxygen delivery to body tissues. These crucial functions are achieved principally by renin‐producing cells located at the entrance of the glomeruli, therefore named juxtaglomerular (JG) cells (Sequeira‐Lopez & Gomez, 2021), and EPO‐producing fibroblasts located in the renal interstitium (Kaneko et al., 2022). Renin is a centrepiece of the renin–angiotensin–aldosterone system (RAAS) and blockade strategies targeting the RAAS have led to the development of widely‐used clinical drugs for the treatment of high blood pressure, heart failure, diabetes and chronic kidney disease progression (Zaman et al., 2002).…”

Section: Introductionmentioning

confidence: 99%

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Neuropilin‐1 regulates renin synthesis in juxtaglomerular cells

Shen,

Lotenberg,

Zaworski

et al. 2024

The Journal of Physiology

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Renin is the key enzyme of the systemic renin–angiotensin–aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin‐1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero‐Cre (P0‐Cre) to abrogate Nrp1 constitutively in P0‐Cre lineage‐labelled cells of the kidney. We found that the P0‐Cre precursor cells differentiate into renin‐producing JG cells. We employed a lineage‐tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell‐autonomous role for NRP1 in JG cell function. Nrp1‐deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0‐Cre–expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. imageKey points Renin is a centrepiece of the renin–angiotensin–aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin‐1 (NRP1) is a conserved membrane‐bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell‐specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin‐producing cells in the kidney and may open new avenues for therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Neuropilin‐1 regulates renin synthesis in juxtaglomerular cells

Shen,

Lotenberg,

Zaworski

et al. 2024

The Journal of Physiology

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“…On the other hand, the dysregulated hematopoietic process is associated with organ damage in fibrotic diseases. Firstly, erythropoietin (Epo)-producing fibroblasts in the kidney transdifferentiate into myofibroblasts during kidney fibrosis, leading to anemia due to Epo deficiency [ 43 , 44 ]. Secondly, altered fibrosis-related cytokines, such as interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), contribute to the deficiency and dysfunction of hematopoietic stem cells (HSCs) that ultimately result in decreased erythropoiesis [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Anemia Is an Indicator for Worse Organ Damage Trajectories in Patients with Systemic Sclerosis: A Retrospective Study

Jiang

et al. 2022

JCM

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It is important for clinicians to determine the risk of worsening trajectories in SSc patients. The Scleroderma Clinical Trials Consortium (SCTC) Damage Index (DI) has been developed to quantify organ damage and shows good capability for mortality and morbidity prediction in patients with SSc. This retrospective study aimed to describe the SCTC-DI in Chinese SSc patients and to find features predicting worse organ damage trajectories based on SCTC-DI. A total of 433 SSc patients who met the inclusion criteria in the Peking University Third Hospital (PKUTH-SSc) and People’s Hospital SSc cohort (PKUPH-SSc) were recruited for our study. Organ damage was relatively mild in our Chinese SSc cohort compared to other cohorts, with a mean SCTC-DI of 5.21 ± 4.60. We used both SCTC-DI ≥ 6 and ≥4 to define the high burden of organ damage and established two risk models by the LASSO algorithm, which revealed good identification of high organ damage burden (AUC = 0.689, 95% CI 0.636 to 0.742, p < 0.001 in SCTC-DI ≥ 6 model; AUC = 0.694, 95% CI 0.641 to 0.746, p < 0.001 in modified SCTC-DI ≥ 4 model). The anemia index at the baseline was included in these two models and was also independently related to organ damage progression (HR = 1.75, 95% CI 1.16 to 2.66, p = 0.008). In addition, the presence of an anti-Scl-70 autoantibody was also a predictor of progression (HR = 1.91, 95% CI 1.22 to 2.99, p = 0.005). In conclusion, anemia at the baseline was an important indicator for worse organ damage trajectories in SSc patients. We recommend using hemoglobin as a potential biomarker to evaluate organ damage in SSc patients.

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“…We found that in aged, injured kidneys, fibroblasts have crucial roles in TLS formation and maturation 54 . In young, injured kidneys, resident fibroblasts transdifferentiate into scar-producing myofibroblasts at the cost of physiological erythropoietin production, leading to fibrosis and renal anaemia, which are common pathological conditions in CKD [172][173][174] . In aged, injured kidneys, fibroblasts also transdifferentiate into TLS-related heterogeneous fibroblasts with distinct phenotypes 7 (Fig.…”

Section: Chronic Inflammatory Diseases and Ageingmentioning

confidence: 99%

The roles of tertiary lymphoid structures in chronic diseases

et al. 2023

Self Cite

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Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that drive antigen-specific immune responses at sites of chronic inflammation. Unlike secondary lymphoid organs such as lymph nodes, TLSs lack capsules and have their own unique characteristics and functions. The presumed influence of TLSs on the disease course has led to widespread interest in obtaining a better understanding of their biology and function. Studies using single-cell analyses have suggested heterogeneity in TLS composition and phenotype, and consequently, functional correlates with disease progression are sometimes conflicting. The presence of TLSs correlates with a favourable disease course in cancer and infection. Conversely, in autoimmune diseases and chronic age-related inflammatory diseases including chronic kidney disease, the presence of TLSs is associated with a more severe disease course. However, the detailed mechanisms that underlie these clinical associations are not fully understood. To what extent the mechanisms of TLS development and maturation are shared across organs and diseases is also still obscure. Improved understanding of TLS development and function at the cellular and molecular levels may enable the exploitation of these structures to improve therapies for chronic diseases, including chronic kidney disease.• In autoimmunity, chronic inflammation and ageing, the presence of TLSs correlates with pathological conditions and a more severe disease course.• Functional characterization of TLSs in human diseases and the development of interventions to induce or reduce TLSs could lead to promising therapeutic avenues.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Lineage tracing analysis defines erythropoietin-producing cells as a distinct subpopulation of resident fibroblasts with unique behaviors

Cited by 17 publications

References 33 publications

Neuropilin‐1 regulates renin synthesis in juxtaglomerular cells

Neuropilin‐1 regulates renin synthesis in juxtaglomerular cells

Anemia Is an Indicator for Worse Organ Damage Trajectories in Patients with Systemic Sclerosis: A Retrospective Study

The roles of tertiary lymphoid structures in chronic diseases

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