Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis

Buhl, Eva Miriam; Djudjaj, Sonja; Klinkhammer, Barbara M.; Ermert, Katja; Puelles, Victor G.; Lindenmeyer, Maja T.; Cohen, Clemens D.; He, Chaoyong; Borkham-Kamphorst, Erawan; Weiskirchen, Ralf; Denecke, Bernd; Trairatphisan, Panuwat; Sáez-Rodríguez, Julio; Huber, Tobias B.; Olson, Lorin E.; Floege, Jürgen

doi:10.15252/emmm.201911021

Cited by 55 publications

(46 citation statements)

References 90 publications

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“…However, no significant overlap was found with other cellular markers, such as CD31 and F4/80, indicating that His-tagged R-III was not randomly distributed in different types of cells but successfully delivered to Cygb/STAP-positive RSCs. PDGFR-β has been shown to be expressed in myofibroblasts and renal mesenchymal cells, including mesangial cells, interstitial fibroblasts and pericytes, and vascular smooth musle cells [ 36 ]. Intriguingly, ~55% of interstitial PDGFR-β + cells expressed Cygb/STAP ( Figure 6 C).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis

et al. 2020

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Interstitial fibrosis is a common feature of chronic kidney disease, and platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells are reportedly the major source of scar-producing myofibroblasts. We had previously demonstrated that albumin and its derivative R-III (a retinol-binding protein-albumin domain III fusion protein) inhibited the transdifferentiation/activation of hepatic stellate cells (HSCs) to myofibroblasts and that R-III administration reduced liver fibrosis. In this study, we isolated cells (referred to as renal stellate cells, RSCs) from rat kidney tissues using the HSC isolation protocol and compared their morphological and biochemical characteristics with those of HSCs. RSCs shared many characteristics with HSCs, such as storage of vitamin A-containing lipid droplets and expression of HSC markers as well as pericyte markers. RSCs underwent spontaneous transdifferentiation into myofibroblasts in in vitro culture, which was inhibited by albumin expression or R-III treatment. We also evaluated the therapeutic effects of R-III in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Injected R-III localized predominantly in cytoglobin/stellate cell activation-associated protein (Cygb/STAP)-positive cells in the kidney and reduced renal fibrosis. These findings suggest that RSCs can be recognized as the renal counterparts of HSCs and that RSCs represent an attractive therapeutic target for anti-fibrotic therapy.

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Section: Resultsmentioning

confidence: 99%

“…Further study is required to address this issue, but there is a serious technical problem that there are no specific markers for stellate cells and pericytes. Commonly used markers, including PDGFR-β, NG2, and Cygb/STAP, are expressed in different types of interstitial, mesenchymal stromal cells [ 36 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis

et al. 2020

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“…During fibrosis, fibroblasts begin to act autonomously and independently of tubular and leukocyte inflammation (Leaf and Duffield, 2017 ). Indeed, recently Buhl et al have elegantly shown that activation of fibroblasts per se is sufficient to drive progressive fibrosis and systemic features of CKD (Buhl et al, 2020 ), independent of any surrounding tubular and interstitial pathologies.…”

Section: Activation Of Fibroblastsmentioning

confidence: 99%

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Hewitson

Smith

2021

Front. Physiol.

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Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.

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“…However, BMPER did not directly improve renal tubular apoptosis and EMT caused by ureteral obstruction. Recent studies have shown that fibroblasts and excessively deposited extracellular matrix can cause tubule epithelial atrophy (Buhl et al, 2020 ), so we speculate that the preservation of tubule integrity by BMPER is due to its anti-fibrotic effect.…”

Section: Discussionmentioning

confidence: 75%

BMPER Ameliorates Renal Fibrosis by Inhibiting Tubular Dedifferentiation and Fibroblast Activation

Xie¹,

Xia

Wang

et al. 2021

Front. Cell Dev. Biol.

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Tubulointerstitial fibrosis is both a pathological manifestation of chronic kidney disease and a driving force for the progression of kidney disease. A previous study has shown that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) is involved in lung fibrogenesis. However, the role of BMPER in renal fibrosis remains unknown. In the present study, the expression of BMPER was examined by real-time PCR, Western blot and immunohistochemical staining. The in vitro effects of BMPER on tubular dedifferentiation and fibroblast activation were analyzed in cultured HK-2 and NRK-49F cells. The in vivo effects of BMPER were dissected in unilateral ureteral obstruction (UUO) mice by delivery of BMPER gene via systemic administration of plasmid vector. We reported that the expression of BMPER decreased in the kidneys of UUO mice and HK-2 cells. TGF-β1 increased inhibitor of differentiation-1 (Id-1) and induced epithelial mesenchymal transition in HK-2 cells, and knockdown of BMPER aggravated Id-1 up-regulation, E-cadherin loss, and tubular dedifferentiation. On the contrary, exogenous BMPER inhibited Id-1 up-regulation, prevented E-cadherin loss and tubular dedifferentiation after TGF-β1 exposure. In addition, exogenous BMPER suppressed fibroblast activation by hindering Erk1/2 phosphorylation. Knockdown of low-density lipoprotein receptor-related protein 1 abolished the inhibitory effect of BMPER on Erk1/2 phosphorylation and fibroblast activation. Moreover, delivery of BMPER gene improved renal tubular damage and interstitial fibrosis in UUO mice. Therefore, BMPER inhibits TGF-β1-induced tubular dedifferentiation and fibroblast activation and may hold therapeutic potential for tubulointerstitial fibrosis.

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Dysregulated mesenchymal PDGFR‐β drives kidney fibrosis

Cited by 55 publications

References 90 publications

Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis

Inhibition of Renal Stellate Cell Activation Reduces Renal Fibrosis

A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

BMPER Ameliorates Renal Fibrosis by Inhibiting Tubular Dedifferentiation and Fibroblast Activation

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