TITLE

A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy

AUTHOR(S)
He, Bing; Österholm, Anne-May; Ojala, Juha R. M.; Andersson, Ann-Charlotte; Tryggvason, Karl
PUB. DATE
February 2013
SOURCE
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
We have previously reported genetic association of a single nucleotide polymorphism (SNP), rs1866813, at 3q locus with increased risk of diabetic nephropathy (DN). The SNP is located approximately 70 kb downstream of a cluster of four genes. This raises a question how the remote noncoding polymorphism affects the risk of DN. In this study, we tested a long-range regulatory potential of this variant by a series of experiments. In a luciferase assay, two alleles of the SNP showed differential effects on the luciferase activity in transfected cells in vitro. Using transgenic zebrafish, we further demonstrated in vivo that two alleles of the SNP differentially regulated GFP expression in zebrafish podocytes. Immunofluorescence staining and Western blotting verified that only Nck1 of the four nearby genes was predominantly expressed in mouse glomeruli as well as in podocytes. Furthermore, genotypes of the SNP rs1866813 were correlated with NCK1 expression in immortalized lymphocytes from diabetic patients. The risk allele was associated with increased NCK1 expression compared to the non-risk allele, consistent with the results of the reporter-based studies. Interestingly, differential expression of glomerular Nck1 between mouse strains carrying the nephropathy-prone 129/Sv allele and nephropathy-resistant C57BL/6 allele was also observed. Our results show that the DN-associated SNP rs1866813 is a remote cis-acting variant differentially regulating glomerular NCK1 expression. This finding implicates an important role for glomerular NCK1 in DN pathogenesis under hyperglycemia.
ACCESSION #
87624584

 

Related Articles

  • CD2AP is associated with end-stage renal disease in patients with type 1 diabetes. Hyvönen, Mervi E.; Ihalmo, Pekka; Sandholm, Niina; Stavarachi, Monica; Forsblom, Carol; McKnight, Amy Jayne; Lajer, Maria; Maestroni, Anna; Lewis, Gareth; Tarnow, Lise; Maestroni, Silvia; Zerbini, Gianpaolo; Parving, Hans-Henrik; Maxwell, Alexander P.; Groop, Per-Henrik; Lehtonen, Sanna // Acta Diabetologica;Dec2013, Vol. 50 Issue 6, p887 

    CD2-associated protein (CD2AP) is essential for podocyte function. CD2AP mutations have been found in patients with focal segmental glomerulosclerosis, a disease histologically resembling diabetic nephropathy and often progressing to end-stage renal disease (ESRD). We hypothesised that...

  • Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Shahzad, Khurrum; Bock, Fabian; Dong, Wei; Wang, Hongjie; Kopf, Stefan; Kohli, Shrey; Al-Dabet, Moh'd Mohanad; Ranjan, Satish; Wolter, Juliane; Wacker, Christian; Biemann, Ronald; Stoyanov, Stoyan; Reymann, Klaus; Söderkvist, Peter; Groß, Olaf; Schwenger, Vedat; Pahernik, Sascha; Nawroth, Peter P; Gröne, Herman-Josef; Madhusudhan, Thati // Kidney International;Jan2015, Vol. 87 Issue 1, p74 

    Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic...

  • mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. Inoki, Ken; Mori, Hiroyuki; Junying Wang; Suzuki, Tsukasa; SungKi Hong; Sei Yoshida; Blattner, Simone M.; Ikenoue, Tsuneo; Rüegg, Markus A.; Hall, Michael N.; Kwiatkowski, David J.; Rastaldi, Maria P.; Huber, Tobias B.; Kretzler, Matthias; Holzman, Lawrence B.; Wiggins, Roger C.; Kun-Liang Guan; Wang, Junying; Hong, SungKi; Yoshida, Sei // Journal of Clinical Investigation;Jun2011, Vol. 121 Issue 6, p2181 

    Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte...

  • Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. Gödel, Markus; Hartleben, Björn; Herbach, Nadja; Shuya Liu; Zschiedrich, Stefan; Shun Lu; Debreczeni-Mór, Andrea; Lindenmeyer, Maja T.; Rastaldi, Maria-Pia; Hartleben, Götz; Wiech, Thorsten; Fornoni, Alessia; Nelson, Robert G.; Kretzler, Matthias; Wanke, Rüdiger; Pavenstädt, Hermann; Kerjaschki, Dontscho; Cohen, Clemens D.; Hall, Michael N.; Rüegg, Markus A. // Journal of Clinical Investigation;Jun2011, Vol. 121 Issue 6, p2197 

    Chronic glomerular diseases, associated with renal failure and cardiovascular morbidity, represent a major health issue. However, they remain poorly understood. Here we have reported that tightly controlled mTOR activity was crucial to maintaining glomerular podocyte function, while...

  • Heparanase Is Essential for the Development of Diabetic Nephropathy in Mice. Gil, Natali; Goldberg, Rachel; Neuman, Tzahi; Garsen, Marjolein; Zcharia, Eyal; Rubinstein, Ariel M.; Van Kuppevelt, Toin; Meirovitz, Amichay; Pisano, Claudio; Jin-Ping Li; Van der Vlag, Johan; Vlodavsky, Israel; Elkin, Michael // Diabetes;Jan2012, Vol. 61 Issue 1, p208 

    Diabetic nephropathy (DN) is the major life-threatening complication of diabetes. Abnormal permselectivity of glomerular basement membrane (GBM) plays an important role in DN pathogenesis. Heparanase is the predominant enzyme that degrades heparan sulfate (HS), the main polysaccharide of the...

  • Renoprotective role of the vitamin D receptor in diabetic nephropathy. Zhang, Z.; Sun, L.; Wang, Y.; Ning, G.; Minto, A. W.; Kong, J.; Quigg, R. J.; Li, Y. C. // Kidney International;Jan2008, Vol. 73 Issue 2, p163 

    1,25-Dihydroxyvitamin D3 negatively regulates the renin–angiotensin system (RAS), which plays a critical role in the development of diabetic nephropathy. We tested if mice lacking the vitamin D receptor (VDR) are more susceptible to hyperglycemia-induced renal injury. Diabetic VDR...

  • Glomerular cell death and inflammation with high-protein diet and diabetes. Meek, Rick L.; LeBoeuf, Renee C.; Saha, Sandeep A.; Alpers, Charles E.; Hudkins, Kelly L.; Cooney, Sheryl K.; Anderberg, Robert J.; Tuttle, Katherine R. // Nephrology Dialysis Transplantation;Jul2013, Vol. 28 Issue 7, p1711 

    Background Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to...

  • Genome-wide association studies in mice. Flint, Jonathan; Eskin, Eleazar // Nature Reviews Genetics;Nov2012, Vol. 13 Issue 11, p807 

    Genome-wide association studies (GWASs) have transformed the field of human genetics and have led to the discovery of hundreds of genes that are implicated in human disease. The technological advances that drove this revolution are now poised to transform genetic studies in model organisms,...

  • Fine-Scale Maps of Recombination Rates and Hotspots in the Mouse Genome. Brunschwig, Hadassa; Levi, Liat; Ben-David, Eyal; Williams, Robert W.; Yakir, Benjamin; Shifman, Sagiv // Genetics;Jul2012, Vol. 191 Issue 3, p757 

    Recombination events are not uniformly distributed and often cluster in narrow regions known as recombination hotspots. Several studies using different approaches have dramatically advanced our understanding of recombination hotspot regulation. Population genetic data have been used to map and...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics