uPAR isoform 2 forms a dimer and induces severe kidney disease in mice

Wei, Changli; Li, Jing; Adair, Brian D.; Zhu, Ke; Cai, Jian; Merchant, Michael L.; Samelko, Beata; Liao, Zhongji; Koh, Kyung Bong; Tardi, Nicholas J.; Dande, Ranadheer R.; Liu, Shuangxin; Ma, Jianchao; DiBartolo, Salvatore; Hägele, Stefan; Peev, Vasil; Hayek, Salim S.; Cimbaluk, David; Tracy, Melissa; Klein, Jon B.; Sever, Sanja; Shattil, Sanford J.; Arnaout, M. Amin; Reiser, Jochen

doi:10.1172/jci124793

Cited by 58 publications

(67 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Inflammation and oxidative stress are central components of the pathogenesis of acute kidney injury, implicating multiple subtypes of immune cells. 8,9 Evidence of a pathway linking the bone marrow to kidney injury has emerged, involving soluble urokinase plasminogen activator receptor (suPAR) 7,[10][11][12][13][14][15][16][17] -the circulating form of a glycosylphosphatidylinositol-anchored three-domain membrane protein. This receptor is normally expressed at very low levels on a variety of cells, including endothelial cells, podocytes, and, with induced expression, immunologically active cells such as monocytes and lymphocytes.…”

Section: Results-mentioning

confidence: 99%

Soluble Urokinase Receptor and Acute Kidney Injury

et al. 2020

Self Cite

View full text Add to dashboard Cite

BACKGROUND-Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS-We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.

show abstract

Section: Results-mentioning

confidence: 99%

Soluble Urokinase Receptor and Acute Kidney Injury

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…From a translational perspective, this domain flexibility also proved essential for the development of a small 9-mer peptide targeting an intermediate conformation in uPAR [28,36] and this assisted its further maturation into a PET-probe currently used for non-invasive imaging of uPAR expression in patients with malignant solid tumors [37][38][39]. Moreover, the dimer of uPAR isoform 2 was reported to induce kidney diseases in mice [40].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

et al. 2020

View full text Add to dashboard Cite

Ly6/uPAR/α-neurotoxin domain (LU-domain) is characterized by the presence of 4-5 disulfide bonds and three flexible loops that extend from a core stacked by several conversed disulfide bonds (thus also named three-fingered protein domain). This highly structurally stable protein domain is typically a protein-binder at extracellular space. Most LU proteins contain only single LU-domain as represented by Ly6 proteins in immunology and α-neurotoxins in snake venom. For Ly6 proteins, many are expressed in specific cell lineages and in differentiation stages, and are used as markers. In this study, we report the crystal structures of the two LU-domains of human C4.4A alone and its complex with a Fab fragment of a monoclonal anti-C4.4A antibody. Interestingly, both structures showed that C4.4A forms a very compact globule with two LU-domain packed face to face. This is in contrast to the flexible nature of most LU-domain-containing proteins in mammals. The Fab combining site of C4.4A involves both LU-domains, and appears to be the binding site for AGR2, a reported ligand of C4.4A. This work reports the first structure that contain two LU-domains and provides insights on how LU-domains fold into a compact protein and interacts with ligands.

show abstract

“…). Note that these msuPAR2‐Tg mice acquired a renal pathology characteristic of FSGS . Taken together, these findings indicate that although an elevated circulating suPAR level causes kidney glomerular sclerosis, it does not lead to any obvious liver fibrosis in mice.…”

Section: Role Of Supar In the Management Of Liver Diseasementioning

confidence: 53%

“…Moreover, as a biomarker, we found that baseline suPAR levels predict the incidence and progression of chronic kidney disease . To uncover the mechanisms underlying the multifaceted functions of suPAR in kidney disease, we developed two suPAR transgenic (Tg) mouse models, msuPAR1‐Tg for uPAR isoform 1 (canonical form) and msuPAR2‐Tg for isoform 2 (secreted form), in which suPAR is driven by adipocyte protein 2 (AP2) promoter and released into blood circulation thereafter . With circulating suPAR evidently increased in both msuPAR‐Tg models, we examined liver tissues for any functional and histological changes.…”

Section: Role Of Supar In the Management Of Liver Diseasementioning

confidence: 99%