Nop-7-associated 2 (NSA2), a candidate gene for diabetic nephropathy, is involved in the TGFβ1 pathway

TY - JOUR

T1 - Nop-7-associated 2 (NSA2), a candidate gene for diabetic nephropathy, is involved in the TGFβ1 pathway

AU - Shahni, Rojeen

AU - Czajka, Anna

AU - Mankoo, Baljinder S.

AU - Guvenel, Aleks Kamer

AU - King, Aileen J.

AU - Malik, Afshan N.

PY - 2013/3

Y1 - 2013/3

N2 - We recently showed that Nop-7-associated 2 (NSA2) originally described in yeast as a nuclear protein involved in ribosomal biogenesis, is a hyperglycemia induced gene involved in diabetic nephropathy [Shahni et al., 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. Diabetologia 2012;55(March(3)):825-34]. However the function of NSA2 in the cell remains unknown. In the current paper we investigate the possible mechanisms for the involvement of NSA2 in diabetic nephropathy by testing the hypothesis that NSA2 expression is linked to the TGF beta 1 pathway. Both TGF beta 1 and NSA2 mRNAs were significantly up-regulated in cultured renal mesangial cells in response to high glucose, in mouse kidneys during hyperglycemia, and in developing kidneys of mouse embryos during mesenchymal to epithelial transition. Surprisingly, the previously described nuclear NSA2 protein was predominantly located in the cytosol of cultured renal cells. Exogenous TGF beta 1 could elevate NSA2 mRNA/protein levels in cultured mesangial cells and could also affect the cellular localization of NSA2, causing the predominantly cytosolic NSA2 protein to rapidly translocate to the nucleus. Increased NSA2 nuclear staining was seen in diabetic mouse kidneys compared to control kidneys. Knock-down of NSA2 expression using RNA interference resulted in significantly decreased TGF beta 1 mRNA/protein, almost abolished TGF beta 1 activity, and resulted in significantly reduced mRNA levels of the TGF beta 1 downstream gene fibronectin. Our data suggest that NSA2 is acting upstream of the TGF beta 1 pathway and that NSA2 is needed for TGF beta 1 expression and transcriptional activity. In summary, NSA2, which increases in diabetic nephropathy, may be involved in the actions of TGF beta 1 and contribute to the development of diabetic nephropathy.

AB - We recently showed that Nop-7-associated 2 (NSA2) originally described in yeast as a nuclear protein involved in ribosomal biogenesis, is a hyperglycemia induced gene involved in diabetic nephropathy [Shahni et al., 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. Diabetologia 2012;55(March(3)):825-34]. However the function of NSA2 in the cell remains unknown. In the current paper we investigate the possible mechanisms for the involvement of NSA2 in diabetic nephropathy by testing the hypothesis that NSA2 expression is linked to the TGF beta 1 pathway. Both TGF beta 1 and NSA2 mRNAs were significantly up-regulated in cultured renal mesangial cells in response to high glucose, in mouse kidneys during hyperglycemia, and in developing kidneys of mouse embryos during mesenchymal to epithelial transition. Surprisingly, the previously described nuclear NSA2 protein was predominantly located in the cytosol of cultured renal cells. Exogenous TGF beta 1 could elevate NSA2 mRNA/protein levels in cultured mesangial cells and could also affect the cellular localization of NSA2, causing the predominantly cytosolic NSA2 protein to rapidly translocate to the nucleus. Increased NSA2 nuclear staining was seen in diabetic mouse kidneys compared to control kidneys. Knock-down of NSA2 expression using RNA interference resulted in significantly decreased TGF beta 1 mRNA/protein, almost abolished TGF beta 1 activity, and resulted in significantly reduced mRNA levels of the TGF beta 1 downstream gene fibronectin. Our data suggest that NSA2 is acting upstream of the TGF beta 1 pathway and that NSA2 is needed for TGF beta 1 expression and transcriptional activity. In summary, NSA2, which increases in diabetic nephropathy, may be involved in the actions of TGF beta 1 and contribute to the development of diabetic nephropathy.

KW - NSA2

KW - TGF beta 1

KW - Hyperglycemia

KW - Nuclear translocation

KW - Diabetic nephropathy

KW - GROWTH-FACTOR-BETA

KW - GLOMERULAR MESANGIAL CELLS

KW - TGF-BETA

KW - GLUCOSE REGULATION

KW - PROTEIN-SYNTHESIS

KW - URETERAL BUD

KW - EXPRESSION

KW - KIDNEY

KW - RECEPTOR

KW - PATHOGENESIS

U2 - 10.1016/j.biocel.2012.11.020

DO - 10.1016/j.biocel.2012.11.020

M3 - Article

C2 - 23220173

SN - 1357-2725

VL - 45

SP - 626

EP - 635

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

IS - 3

M1 - N/A

ER -