Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Lu, Ailing; Miao, Mi; Schoeb, Trenton R.; Agarwal, Anupam; Murphy-Ullrich, Joanne E.

doi:10.1016/j.ajpath.2011.02.039

Cited by 81 publications

(83 citation statements)

References 74 publications

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“…In a streptozotocin-induced model of diabetic nephropathy, a PDE inhibitor suppressed TSP1 expression and ameliorated kidney injury (95), and exogenous NO decreased TSP1 production in cultured endothelial cells (83). Also, in a mouse model of diabetic nephropathy, the LSKL sequence from the latency-associated peptide, which inhibits TSP1-mediated latent TGF-␤1 activation, improved renal function (62). Finally, in kidney biopsies from human subjects with diabetic nephropathy both glomerular and cortical TSP1 expression was associated with disease (32).…”

Section: Tsp1 and Cd47 In Renal Diseasementioning

confidence: 99%

Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

Rogers

Yao

Novelli

et al. 2012

American Journal of Physiology-Renal Physiology

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Ischemia-reperfusion injury (IRI) remains a significant source of early and delayed renal transplant failure. Therapeutic interventions have yet to resolve this ongoing clinical challenge although the reasons for this remain unclear. The cell surface receptor CD47 is widely expressed on vascular cells and in tissues. It has one known soluble ligand, the stress-released matricellular protein thrombospondin-1 (TSP1). The TSP1-CD47 ligand receptor axis controls a number of important cellular processes, inhibiting survival factors such as nitric oxide, cGMP, cAMP, and VEGF, while activating injurious pathways such as production of reactive oxygen species. A role of CD47 in renal IRI was recently revealed by the finding that the TSP1-CD47 axis is induced in renal tubular epithelial cells (RTEC) under hypoxia and following IRI. The absence of CD47 in knockout mice increases survival, mitigates RTEC damage, and prevents subsequent kidney failure. Conversely, therapeutic blockade of TSP1-CD47 signaling provides these same advantages to wild-type animals. Together, these findings suggest an important role for CD47 in renal IRI as a proximate promoter of injury and as a novel therapeutic target.

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Section: Tsp1 and Cd47 In Renal Diseasementioning

confidence: 99%

Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

Rogers

Yao

Novelli

et al. 2012

American Journal of Physiology-Renal Physiology

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“…We also used a mass spectrometry-based assay for serum creatinine at day 28 after IR-AKI. This assay is more sensitive to detect differences in serum creatinines between 0.1 and 0.3 mg/dl (requires ϳ10 l of serum; performed by the University of Alabama at Birmingham O'Brien Center for Acute Kidney Injury) (32,55). PM was administered to mice at estimated doses of 500 and 1,000 mg·kg Ϫ1 ·day Ϫ1 in the drinking water (2.5 and 5 g/ml drinking water based on average 25-g mice drinking 5 ml of water/day).…”

Section: Ir-aki In Micementioning

confidence: 99%

“…4A), suggesting that, despite improvement in tubular injury at early time points, PM does not improve early functional recovery after IR-AKI. To assess the long-term effects of PM on functional recovery after IR-AKI, we used a MS-based measurement that detects serum creatinine values in the lower end of the normal range described for mice (32,55). As previously reported (32,55), baseline levels of serum creatinine in uninjured mice were significantly lower when measured by MS vs. enzymatic cascade (EC) assay that we used day 9 after IR-AKI (MS: n ϭ 8, mean 0.09 Ϯ 0.009 mg/dl; EC: n ϭ 26, mean 0.31 Ϯ 0.015 mg/dl, t-test, P Ͻ 0.0001).…”

mentioning

confidence: 99%

“…To assess the long-term effects of PM on functional recovery after IR-AKI, we used a MS-based measurement that detects serum creatinine values in the lower end of the normal range described for mice (32,55). As previously reported (32,55), baseline levels of serum creatinine in uninjured mice were significantly lower when measured by MS vs. enzymatic cascade (EC) assay that we used day 9 after IR-AKI (MS: n ϭ 8, mean 0.09 Ϯ 0.009 mg/dl; EC: n ϭ 26, mean 0.31 Ϯ 0.015 mg/dl, t-test, P Ͻ 0.0001). Using MS-based measurement of serum creatinine, we saw a reduction in serum creatinine at 28 days after IR-AKI in mice treated with 1,000 mg·kg Ϫ1 ·day Ϫ1 PM compared with vehicle-treated controls (Fig.…”

mentioning

confidence: 99%

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Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Skrypnyk

Voziyan

Yang

et al. 2016

American Journal of Physiology-Renal Physiology

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Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI.

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“…La perfusion de ce peptide, après induction d'une glomérulonéphrite membrano-proliférative chez le rat, réduit l'accumulation de MEC dans les glomérules et le débit de protéinurie [40]. L'injection de LSKL à des souris diabétiques, après une néphrectomie unilatérale, réduit le taux urinaire de TGF- actif, l'expression rénale des protéines Smad2 (mothers against decapentaplegic homolog 2) et -3 phosphorylées, l'accumulation interstitielle de fibronectine, la perte d'expression de la néphrine par les podocytes et l'albuminurie [41]. Enfin, l'injection de LSKL après obstruction urétérale unilatérale diminue l'expression rénale de Smad2 phosphorylée, les lésions tubulaires, la fibrose interstitielle, et s'associe à une réduction de l'expression de l'ARNm de tsp-1 et de sa protéine, suggérant un rétrocontrôle positif du TGF- actif sur l'expression de la TSP-1 [42].…”

Section: Expression De La Thrombospondine-1 Au Cours Des Néphropathieunclassified

Rôle de la thrombospondine-1 dans le développement des maladies rénales

et al. 2013

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> La thrombospondine-1 (TSP-1) est une glycoprotéine matricielle de 450 kDa qui possède des propriétés anti-angiogéniques, pro-apoptotiques et immunomodulatrices. Il s'agit aussi d'un activateur endogène majeur du facteur profibrosant TGF- (transforming growth factor-b). Son expression, très faible dans le parenchyme sain, augmente significativement après une agression rénale. L'inhibition de ses différents domaines par des anticorps ou peptides spécifiques, le blocage de son expression par des oligonucléotides antisens et l'utilisation de souris knock-out ont permis d'éclaircir le rôle de la TSP-1 dans des modèles expérimentaux de néphropathie. Ces études ont montré son effet délétère sur la réparation du tissu rénal en favorisant le développement de la fibrose, la raréfaction capillaire et le recrutement des cellules inflammatoires. Ainsi, la TSP-1 représente une cible thérapeutique potentielle pour la prise en charge des maladies rénales chroniques. < sont des glycoprotéines homotrimériques de structure homologue. Les TSP-3 à -5, qui constituent le groupe B, sont des homopentamères. La TSP-1, glycoprotéine de 450 kDa identifiée par une analyse du contenu des granules  des plaquettes stimulées par la thrombine, a été la première décrite en 1971. Son domaine amino-terminal, constitué d'environ 200 acides aminés, se lie à l'héparine, aux protéoglycanes et aux intégrines 31, 41, 51 et 61 (Figure 1). Il assure aussi sa clairance par le récepteur des lipoprotéines de faible densité (LRP). Il existe ensuite un domaine d'oligomérisa-tion, puis un domaine procollagénique identique au domaine de type C du facteur von Willebrand (vWF) qui participe à l'activité anti-angiogénique. Puis intervient le domaine TSR1 (domaine de répétition de type 1) qui est caractérisé par trois répétitions du motif TSPc et qui contient les deux séquences indispensables à l'activation du TGF- (transforming growth factor-b). Ce domaine participe aussi à l'activité anti-angiogénique en interagissant avec les intégrines 1 et le CD36. La partie carboxy-terminale, appelée domaine de signature, hautement conservée au sein de la famille des TSP, comporte des domaines EGF (epidermal growth factor)-like (TSR2) répétés trois fois, suivis de 13 séquences de fixation au calcium. Le domaine globulaire carboxy-terminal lectine-like permet la fixation au récepteur CD47 ou IAP (integrin associated protein) (Figure 1) [1, 2]. Fonctions de la thrombospondine-1 Activation du TGF-bLa TSP-1 est un activateur endogène du TGF- qui est un facteur profibrosant majeur. Elle forme un complexe trimoléculaire avec La thrombospondine-1 (TSP-1) est la première protéine de la famille des thrombospondines (TSP) qui a été décrite, et elle est la plus étudiée. Elle interagit avec de nombreux partenaires et possède une activité anti-angiogénique, pro-apoptotique et immunomodulatrice. Chez l'adulte, l'expression de la TSP-1 se limite aux tissus inflammatoires ou en cours de remodelage ; elle y régule la structure de la matrice extracellulaire, ainsi que le phénotyp...

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Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Cited by 81 publications

References 74 publications

Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

Activated CD47 regulates multiple vascular and stress responses: implications for acute kidney injury and its management

Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Rôle de la thrombospondine-1 dans le développement des maladies rénales

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