title: Elevated levels of renal and circulating Nop-7-associated 2 (NSA2) in rat and mouse models of diabetes, in mesangial cells in vitro and in patients with diabetic nephropathy.
abstract: OBJECTIVE
  We previously found that Nop-7-associated 2 (NSA2), which is involved in ribosomal biogenesis in yeast and is a putative cell cycle regulator in mammalian cells, is elevated in the kidney of Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. Here we tested the hypothesis that elevated NSA2 is involved in diabetic nephropathy (DN).
  
  
  METHODS
  We examined Nsa2/NSA2 expression and NSA2 production in two rodent models of diabetes, in cultured renal glomerular cells, and in diabetic patients with and without nephropathy. Patients with nephropathy who had a history of albuminuria were further divided as responders (DN-NA; DN patients normoalbuminuric at the time of this study with a history of albuminuria) and non-responders (DN-A; diabetic nephropathy patients with albuminuria) to current treatment for albuminuria.
  
  
  RESULTS
  Renal Nsa2/NSA2 mRNA increased in tandem with hyperglycaemia in GK rats, in a streptozotocin-induced mouse model of diabetes, and in human mesangial cells (HMCs) grown in high glucose (p < 0.05). In the mouse model of diabetes, hyperglycaemia resulted in increased Nsa2 expression and NSA2 levels in tubular and glomerular cells and in circulating cells; this increase was normalised by diabetes treatment. Circulating NSA2 mRNA levels were elevated in patients with DN independently of body weight (BMI), glycaemic (HbA(1c)) and haemodynamic (blood pressure) control, and showed an inverse correlation with renal function (GFR, p < 0.05). NSA2 levels were the only variable that showed a significant difference between patients with albuminuria (DN-A) compared with non-albuminuric patients (DN-NA) and diabetic controls (p < 0.05), this increase being independent of all other variables, including GFR.
  
  
  CONCLUSIONS
  We show for the first time that renal and circulating NSA2/NSA2 levels are increased in hyperglycaemia in experimental models of diabetes, and that circulating NSA2 is elevated in DN patients with albuminuria. Further studies will be required to assess whether NSA2 plays a role in the pathogenesis of DN.
authors.affiliation: Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, Hodgkin Building, London Bridge, London SE1 1UL, UK.
authors.forename: R
authors.initials: R
authors.lastname: Shahni
authors.forename: L
authors.initials: L
authors.lastname: Gnudi
authors.forename: A
authors.initials: A
authors.lastname: King
authors.forename: P
authors.initials: P
authors.lastname: Jones
authors.forename: A N
authors.initials: AN
authors.lastname: Malik
mesh_terms: D000328:Adult; D000368:Aged; D000419:Albuminuria / Q000209:etiology; D000818:Animals; D018797:Cell Cycle Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009687:Nuclear Proteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D018797:Cell Cycle Proteins; C547685:NSA2 protein, human; C573125:NSA2 protein, mouse; C573124:NSA2 protein, rat; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
references.citation: Biochem Soc Trans. 2008 Oct;36(Pt 5):941-5
references.pmid: 18793165
references.citation: J Am Soc Nephrol. 2005 Mar;16 Suppl 1:S30-3
references.pmid: 15938030
references.citation: Nephron Exp Nephrol. 2009;112(1):e1-9
references.pmid: 19342868
references.citation: Br Med J (Clin Res Ed). 1983 Feb 19;286(6365):598-602
references.pmid: 6402163
references.citation: Lancet. 1998 Sep 12;352(9131):837-53
references.pmid: 9742976
references.citation: Diabetes Care. 2011 Mar;34(3):691-6
references.pmid: 21273494
references.citation: JAMA. 2002 Nov 27;288(20):2579-88
references.pmid: 12444865
references.citation: Biochem Biophys Res Commun. 2003 Oct 17;310(2):513-21
references.pmid: 14521940
references.citation: Nature. 2001 Dec 13;414(6865):813-20
references.pmid: 11742414
references.citation: Genomics. 1999 Sep 1;60(2):161-71
references.pmid: 10486207
references.citation: J Biol Chem. 2006 Sep 15;281(37):27099-108
references.pmid: 16861225
references.citation: Diabetes. 2007 Sep;56(9):2312-8
references.pmid: 17563059
references.citation: J Am Soc Nephrol. 2007 Apr;18(4):1353-61
references.pmid: 17329575
references.citation: N Engl J Med. 1993 Sep 30;329(14):977-86
references.pmid: 8366922
references.citation: Clin Chem. 2007 Mar;53(3):480-8
references.pmid: 17259236
references.citation: PLoS One. 2008 Aug 13;3(8):e2937
references.pmid: 18698414
references.citation: Diabetes Metab. 2008 Nov;34(5):482-9
references.pmid: 18703370
references.citation: J Korean Med Sci. 2011 Feb;26(2):258-63
references.pmid: 21286018
references.citation: Biochem Biophys Res Commun. 1997 Mar 6;232(1):49-53
references.pmid: 9125149
references.citation: J Am Soc Nephrol. 2005 Jan;16(1):133-43
references.pmid: 15574513
references.citation: Endocr Pract. 2006 Jan-Feb;12 Suppl 1:34-41
references.pmid: 16627378
references.citation: Annu Rev Pathol. 2011;6:395-423
references.pmid: 21261520
references.citation: Am J Kidney Dis. 2001 Aug;38(2):310-6
references.pmid: 11479157
references.citation: Biochem Biophys Res Commun. 2010 Jan 1;391(1):651-8
references.pmid: 19932687
references.citation: Am J Physiol Renal Physiol. 2011 Jan;300(1):F219-30
references.pmid: 20943765
references.citation: Nephrol Dial Transplant. 2002 Nov;17(11):2036-7
references.pmid: 12401874
references.citation: Diabetes Care. 2008 Jun;31(6):1177-82
references.pmid: 18344285
references.citation: Mol Biol Cell. 2002 Nov;13(11):4100-9
references.pmid: 12429849
references.citation: Biochem Biophys Res Commun. 2010 Jan 22;391(4):1585-91
references.pmid: 20018174
references.citation: Biochem Biophys Res Commun. 2007 Feb 9;353(2):318-23
references.pmid: 17187760
references.citation: Mol Cell. 2001 Sep;8(3):505-15
references.pmid: 11583614
references.citation: Curr Hypertens Rep. 2010 Oct;12(5):364-8
references.pmid: 20686930
references.citation: Nucleic Acids Res. 2008 Sep;36(15):4988-99
references.pmid: 18658244
references.citation: Biochem Biophys Res Commun. 2009 Apr 10;381(3):367-71
references.pmid: 19309774
references.citation: Biochem Biophys Res Commun. 2007 May 25;357(1):237-44
references.pmid: 17416350
references.citation: Diabetes Metab Res Rev. 2010 Mar;26(3):150-71
references.pmid: 20222150
references.citation: Nature. 2005 Jan 6;433(7021):77-83
references.pmid: 15635413