Inhibition of WISE Preserves Renal Allograft Function

Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xiaowen; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, V. Dan; Williams, Alexia; Valente, Eliane G.; Pretorius, Jim; Stevens, Jennitte; Tipton, Barbara; Winters, Aaron; Graham, Kevin C.; Harriss, L. C.; Baker, Daniel; Damore, Michael A.; Salimi-Moosavi, Hossein; Gao, Yujie; Elkhal, Abdallah; Pászty, Chris; Simonet, W S; Richards, William G.; Tullius, Stefan G.

doi:10.1681/asn.2012010012

Cited by 10 publications

(12 citation statements)

References 37 publications

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“…A ␤-catenin/T cell factor (TCF)-luciferase reporter system was used to measure Wnt signaling activity under various conditions in vitro. For TCF luciferase experiments, 293 Super Top Flash cells (1,30) were grown in DMEM (Cellgro) and seeded in 96-well plates (Costar) at 3.5 ϫ 10 4 cells/well. The following day, reagents were mixed accordingly, incubated at room temperature for 30 min, and then added to cells: recombinant mouse WNT3a and recombinant mouse SFRP5 (R & D Systems) and anti-SFRP5 mAb.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism

Rulifson

Majeti

Xiong

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity. Thus, we generated a monoclonal antibody (mAb) against SFRP5 to ascertain the effect of SFRP5 inhibition in vivo. Congruent with SFRP5 overexpression worsening blood glucose levels and glucose intolerance, anti-SFRP5 mAb therapy improved these phenotypes in vivo. The results from both the overexpression and mAb inhibition studies suggest a role for SFRP5 in glucose metabolism and pancreatic ␤-cell function and thus establish the use of an anti-SFRP5 mAb as a potential approach to treat type 2 diabetes. secreted frizzled-related protein 5; diabetes; obesity; pancreatic ␤-cell; Wnt GENOME-WIDE ASSOCIATION STUDIES (GWAS) have identified multiple genomic loci associated with susceptibility to type 2 diabetes (T2D). One such locus reported by several groups to be highly associated with T2D risk, transcription factor 7-like 2 (TCF7L2), is located in the noncoding region of a gene in the Wnt-signaling pathway (10,12,35,36,38,39,46). Although expressed in many tissues, the variant in TCF7L2 associates with impaired pancreatic ␤-cell insulin secretion and ␤-cell survival (8,9,17,18,20,21,33,37,40,41,47). The commonality of the TCF7L2 variants among the population and across ethnicities, combined with the reported associated risk, places TCF7L2 as the strongest identified genetic risk factor for T2D (12,44). Findings such as this fuel the incentive to better understand how modulation of the Wnt signaling pathway drives T2D pathogenesis and determine whether a Wnt pathway-associated protein could be a suitable therapeutic target for treating this disease.Secreted frizzled-related proteins (SFRPs) comprise a family of secreted proteins that contain an NH 2 terminus cysteine-rich domain (CRD) homologous to that found in the Wnt-binding seven-transmembrane receptor, Frizzled (24, 31). Via their CRD, SFRPs bind to Wnt proteins, thereby blocking their interactions with Frizzled and inhibiting canonical Wnt signaling (7). Of the family members, Sfrp5 mRNA expression in mice has been shown to be sensitive to metabolic queues and changes with fat mass expansion (16,25,27). The role of SFRP5 in metabolism, however, remains unclear due to contradictory phenotypes observed with different lines of Sfrp5-deficient mice. In the first published study, Sfrp5-deficient mice were reported to exhibit severe glucose intolerance and hepatic steatosis upon consumption of a high-fat/high-sugar diet; both phenotypes were reversed upon adenovirus-mediated SFRP5 overexpression (27). The authors proposed that, in the context ...

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Section: Methodsmentioning

confidence: 99%

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism

Rulifson

Majeti

Xiong

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Qian et al recently addressed these emerging concepts therapeutically in a similar rat model of renal chronic allograft injury (88). The Wnt inhibitor Wise was expressed in the kidney allograft by day 3 post-transplant and showed increased tissue expression by month 6 post-transplant.…”

Section: Application Of Emerging Concepts In the Ckd-mbd To Kidney Trmentioning

confidence: 99%

“…The Wnt inhibitor Wise was expressed in the kidney allograft by day 3 post-transplant and showed increased tissue expression by month 6 post-transplant. Treatment with a neutralizing anti-Wise antibody throughout the post-transplant period improved renal allograft function and survival, reduced chronic allograft injury scores, reduced inflammatory cell infiltrates, and reduced expression of inflammatory and fibrotic transcripts (88). …”

Section: Application Of Emerging Concepts In the Ckd-mbd To Kidney Trmentioning

confidence: 99%

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder

Seifert

Hruska

2016

Transplantation

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The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well, as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This Overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.

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“…18 WNT signaling can be reactivated locally and transiently as a response to wounding in the kidney and many other tissues. [23][24][25][26][27][28] However, WNT reactivation also occurs in endothelial cells of the kidney and other organs undergoing MVI. 17,18,22 In animal models of native and transplant CKD, WNT reactivation has been widely demonstrated in tubulointerstitial injury leading to progressive interstitial fibrosis and tubular atrophy.…”

Section: Introductionmentioning

confidence: 99%

“…17,18,22 In animal models of native and transplant CKD, WNT reactivation has been widely demonstrated in tubulointerstitial injury leading to progressive interstitial fibrosis and tubular atrophy. [23][24][25][26][27][28] However, WNT reactivation also occurs in endothelial cells of the kidney and other organs undergoing MVI. In models of native CKD as well as autoimmune encephalitis with MVI, endothelial WNT reactivation was associated with increased pro-inflammatory signaling and progressive interstitial fibrosis.…”

Section: Introductionmentioning

confidence: 99%

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

Seifert

Gaut

Guo

et al. 2019

American Journal of Transplantation

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Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and sex. We measured WNT gene expression with a multiplex quantification platform by using digital barcoding, given the importance of WNT reactivation to the response to wounding in the kidney microvasculature and other compartments. Of 210 genes from a commercial WNT panel, 71 were associated with microvascular injury and 79 were associated with allograft failure, with considerable overlap of genes between each set. Molecular pathology identified 46 biopsy specimens with molecular evidence of microvascular injury; 18 (39%) were either C4d negative, donor-specific antibody negative, or had no microvascular injury by histology. The majority of cases with molecular evidence of microvascular injury had poor long-term outcomes.We identified novel WNT pathway genes associated with microvascular injury and

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Inhibition of WISE Preserves Renal Allograft Function

Cited by 10 publications

References 37 publications

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism

Inhibition of secreted frizzled-related protein 5 improves glucose metabolism

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure

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