Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease

Lin, Jingmei; Patel, Sanjeevkumar R.; Cheng, Xu; Cho, Eun Ah; Levitan, Inna; Ullenbruch, Matthew; Phan, Sem H.; Park, John M.; Dressler, Gregory R.

doi:10.1038/nm1217

Cited by 173 publications

(168 citation statements)

References 35 publications

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“…At least seven animals of each genotype were analyzed at each time point. KCP null animals were defined as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

“…Extracellular inhibitors of BMP signaling include vertebrate Chordin, which binds directly to BMPs through the cysteine-rich (CR) domains containing CXXCXC and CCXXC motifs (5,10,19). While Chordin blocks BMP/receptor interactions, the CR domain protein KCP enhances BMP/receptor interactions to in-crease the efficacy of signaling (11). Similarly, the CR domain protein connective tissue growth factor (CTGF) also enhances TGF-␤-mediated signaling while suppressing the BMP-dependent pathway (1).…”

mentioning

confidence: 99%

“…The KCP protein contains 18 cysteine-rich domains and is expressed in the developing kidney at both early and late stages (11). KCP expression corresponds to the formation of epithelial structures within the intermediate mesoderm and to the formation of the proximal tubules in the more developed metanephric kidney.…”

mentioning

confidence: 99%

“…KCP expression corresponds to the formation of epithelial structures within the intermediate mesoderm and to the formation of the proximal tubules in the more developed metanephric kidney. Unlike Chordin or CTGF, KCP enhances BMP-mediated signaling in a paracrine manner by interacting with the type I receptor to facilitate the binding of BMP7 to BMP receptor 1A (11). Mice homozygous for a mutant KCP allele show no gross developmental abnormalities but exhibit enhanced susceptibility to developing renal interstitial fibrosis, a process known to be regulated both by BMPs and by TGF-␤, in two different animal models (11).…”

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confidence: 99%

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The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

Lin¹,

Patel

Wang³

et al. 2006

Molecular and Cellular Biology

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The transforming growth factor ␤ (TGF-␤) superfamily, including the bone morphogenetic protein (BMP) and TGF-␤/activin A subfamilies, is regulated by secreted proteins able to sequester or present ligands to receptors. KCP is a secreted, cysteine-rich (CR) protein with similarity to mouse Chordin and Xenopus laevis Kielin. KCP is an enhancer of BMP signaling in vertebrates and interacts with BMPs and the BMP type I receptor to promote receptor-ligand interactions. Mice homozygous for a KCP null allele are hypersensitive to developing renal interstitial fibrosis, a disease stimulated by TGF-␤ but inhibited by BMP7. In this report, the effects of KCP on TGF-␤/activin A signaling are examined. In contrast to the enhancing effect on BMPs, KCP inhibits both activin A-and TGF-␤1-mediated signaling through the Smad2/3 pathway. These inhibitory effects of KCP are mediated in a paracrine manner, suggesting that direct binding of KCP to TGF-␤1 or activin A can block the interactions with prospective receptors. Consistent with this inhibitory effect, primary renal epithelial cells from KCP mutant cells are hypersensitive to TGF-␤ and exhibit increased apoptosis, dissociation of cadherin-based cell junctions, and expression of smooth muscle actin. Furthermore, KCP null animals show elevated levels of phosphorylated Smad2 after renal injury. The ability to enhance BMP signaling while suppressing TGF-␤ activation indicates a critical role for KCP in modulating the responses between these antiand profibrotic cytokines in the initiation and progression of renal interstitial fibrosis.The transforming growth factor ␤ (TGF-␤) superfamily encodes growth and differentiation factors that regulate a wide variety of cellular processes. The members of the TGF-␤ superfamily include two major branches, bone morphogenetic proteins (BMPs) and TGF-␤s/activins (19). TGF-␤ signaling is initiated by the binding of the ligand to a specific pair of type I and type II transmembrane receptors, leading to the phosphorylation of the cytoplasmic serine/threonine kinase domains (19,25). The type I receptors, also known as activinlinked kinases (ALKs), then transduce signals downstream by phosphorylation of receptor-activated Smad proteins. The Smad family can be divided into three distinct subfamilies: receptor-activated Smads (R-Smad), common-partner Smads (Co-Smad), and inhibitory Smads. Whereas Smad1, Smad5, and Smad8 are phosphorylated by BMP type I receptors (ALK-2, ALK-3, and ALK-6), Smad2 and Smad3 are activated by TGF-␤ and activin type I receptors (ALK-5 and ALK-4). The R-Smad and the Co-Smad (Smad4) form a heterooligomer which translocates into the nucleus and regulates expression of ligand-responsive genes. Inhibitory Smads include Smad6 and Smad7, which prevent the activation of R-and Co-Smad.While members of the TGF-␤ superfamily use similar mechanisms to signal to the nucleus, the two major branches achieve specificity by using different elements. Outside the cell, each ligand of the TGF-␤ superfamily binds to specific pairs of the recept...

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“…At least seven animals of each genotype were analyzed at each time point. KCP null animals were defined as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

Lin¹,

Patel

Wang³

et al. 2006

Molecular and Cellular Biology

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“…119 In contrast, Kielin/chordin-like protein (KCP) protein is an extracellular protein that enhances the activity of BMP7 by amplifying the physical interaction of BMP7 with its receptor. 120 BMP7 is a member of the TGF-b superfamily. [121][122][123] BMP7 binds to three type I receptors, activin-like kinases (Alk) -2, -3 and -6, and a Figure 1 Working hypothesis of combating aging kidney.…”

Section: Perspective: Anti-fibrosis Therapymentioning

confidence: 99%

Pathophysiology of the aging kidney and therapeutic interventions

2012

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Kidneys are among the organs affected by the aging process. Aging kidneys are characterized by progressive scarring and measurable declines in renal function. Deficiencies in renal function are associated with mortality in all populations. Therefore, if the kidneys age at an accelerated rate relative to the other organs in a particular individual, then slowing or reversing the kidney aging process may be a therapeutically useful strategy. In this review, we will discuss the physiology and pathogenesis of kidney aging and analyze potential therapeutic strategies for halting the aging process in the kidneys.

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Kielin/chordin‐like protein enhances induction of osteoblast differentiation by Bone Morphogenetic Protein‐2

et al. 2023

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Bone morphogenetic proteins (BMPs) play a key role in embryonic differentiation for osteoblast and bone formation. Kielin/chordin-like protein (Kcp) is known to enhance the effects of BMP signaling. Here, we present ALP activity, gene expression, and calcification data demonstrating that Kcp affects the differentiation of C2C12 myoblasts into osteoblasts. We report that the presence of Kcp enhances the ability of BMP-2 to induce the differentiation of C2C12 myoblasts into osteoblasts. Additionally, BMP-2-mediated stimulation of phosphorylated Smad1/5 was apparently enhanced in the presence of Kcp. The present findings may contribute to progression toward the clinical use of BMPs for treatment of bone fracture, osteoarthritis, and other similar conditions.Bone morphogenetic proteins (BMPs), secreted signal transmitters that belong to the TGF-b superfamily, are generally known to have effects causing induction of differentiation of stem cells into osteoblasts [1], with several types and various functions reported [2]. For example, BMP-1 promotes collagenous proliferation and cartilage formation [3], while BMP-4 promotes neural plate formation in the embryologic phase, which later develops into the central nervous system [4]. Furthermore, BMP-6 plays an extremely important role in iron homeostasis for formation of hepcidin [5] and BMP-15 promotes follicle formation in the ovaries [6].

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Kielin/chordin-like protein, a novel enhancer of BMP signaling, attenuates renal fibrotic disease

Cited by 173 publications

References 35 publications

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

The Cysteine-Rich Domain Protein KCP Is a Suppressor of Transforming Growth Factor β/Activin Signaling in Renal Epithelia

Pathophysiology of the aging kidney and therapeutic interventions

Kielin/chordin‐like protein enhances induction of osteoblast differentiation by Bone Morphogenetic Protein‐2

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