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Twist2 is a Novel Regulator of Renal Fibrosis
Author(s) -
Nichols LaNita,
GrunzBorgmann Elizabeth,
Parrish Alan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.663.18
Subject(s) - fibrosis , kidney , endocrinology , kidney disease , medicine , plasminogen activator inhibitor 1 , biology , renal function , plasminogen activator
Morphological and functional changes occur in the aging kidney, including the loss of kidney mass and an increase in fibrosis, an abnormal accumulation of the extracellular matrix (ECM). Functional changes include a decrease in glomerular filtration rate (GFR), proteinuria and reduced ability to concentrate urine. Age is a major risk factor for chronic kidney disease (CKD) while kidney dysfunction and fibrosis are hallmarks of CKD. Thus, aging and CKD have many common elements. Male Fischer 344 rats are an excellent animal model as they develop severe renal disease and fibrosis similar to CKD with aging. However, a soy diet started at 16‐months, the age dysfunction is first detected, has been demonstrated to reverse age‐related damage and fibrosis to the kidneys. Sequencing of kidney RNA purified from aged soy‐fed rats, compared to control, found decreased expression of Twist2, a basic Helix‐Loop‐Helix (bHLH) transcription factor. However, rats fed a normal diet had increasing Twist2 expression with age, as compared to young. A stable cell line of Twist2 overexpression was generated in NRK‐52E cells. Again, RNA sequencing revealed the expression of several genes significantly changed, including up‐regulation of Serpine1. Serpine 1 encodes for the serine protease inhibitor, plasminogen activator inhibitor‐1 (PAI‐1). Interestingly, PAI‐1 expression increased with age and parallels increasing Twist2 expression. Increased PAI‐1 expression is associated with increased fibrosis, while PAI‐1 ‐/‐ mice attenuates this affect. Twist2 recognizes the E‐box element, nCAnnTGn, of which the Serpine‐1 promoter has several. Thus, Twist2 is a novel regulator of Serpine1/PAI‐1 and fibrosis in the kidney.