Inhibition of Kirsten-Ras reduces fibrosis and protects against renal dysfunction in a mouse model of chronic folic acid nephropathy

• Published in: Scientific reports Vol. 9; no. 1; pp. 14010 - 10
• Main Authors: Newbury, Lucy J., Wang, Jui-Hui, Hung, Gene, Hendry, Bruce M., Sharpe, Claire C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.09.2019; Nature Publishing Group
• Subjects: 13; 13/89; 631/154/556; 64; 64/60; 692/4022/1585/104; 692/4022/1585/3182; Acute Kidney Injury - complications; Animal models; Animals; Antisense oligonucleotides; Cardiovascular diseases; Cytokines; Disease Models, Animal; End-stage renal disease; Fibrosis; Folic acid; Folic Acid - toxicity; Gene Knockdown Techniques; Humanities and Social Sciences; Jagged-1 Protein - metabolism; K-Ras protein; Kidney - pathology; Kidney diseases; Kidneys; Male; Mice; multidisciplinary; Nephropathy; Polymerase Chain Reaction; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - metabolism; Renal function; Renal Insufficiency, Chronic - chemically induced; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - prevention & control; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-50422-7

Chronic Kidney Disease is a growing problem across the world and can lead to end-stage kidney disease and cardiovascular disease. Fibrosis is the underlying mechanism that leads to organ dysfunction, but as yet we have no therapeutics that can influence this process. Ras monomeric GTPases are master regulators that direct many of the cytokines known to drive fibrosis to downstream effector cascades. We have previously shown that K-Ras is a key isoform that drives fibrosis in the kidney. Here we demonstrate that K-Ras expression and activation are increased in rodent models of CKD. By knocking down expression of K-Ras using antisense oligonucleotides in a mouse model of chronic folic acid nephropathy we can reduce fibrosis by 50% and prevent the loss of renal function over 3 months. In addition, we have demonstrated in vitro and in vivo that reduction of K-Ras expression is associated with a reduction in Jag1 expression; we hypothesise this is the mechanism by which targeting K-Ras has therapeutic benefit. In conclusion, targeting K-Ras expression with antisense oligonucleotides in a mouse model of CKD prevents fibrosis and protects against renal dysfunction.