Pan-Src kinase inhibitor treatment attenuates diabetic kidney injury via inhibition of Fyn kinase-mediated endoplasmic reticulum stress

Abstract

Src family kinases (SFKs) have been implicated in the pathogenesis of kidney fibrosis. However, the specific mechanism by which SFKs contribute to the progression of diabetic kidney disease (DKD) remains unclear. Our preliminary transcriptome analysis suggested that SFK expression was increased in diabetic kidneys and that the expression of Fyn (a member of the SFKs), along with genes related to unfolded protein responses from the endoplasmic reticulum (ER) stress signaling pathway, was upregulated in the tubules of human diabetic kidneys. Thus, we examined whether SFK-induced ER stress is associated with DKD progression. Mouse proximal tubular (mProx24) cells were transfected with Fyn or Lyn siRNA and exposed to high glucose and palmitate (HG-Pal). Streptozotocin-induced diabetic rats were treated with KF-1607, a novel pan-Src kinase inhibitor (SKI) with low toxicity. The effect of KF-1607 was compared to that of losartan, a standard treatment for patients with DKD. Among the SFK family members, the Fyn and Lyn kinases were upregulated under diabetic stress. HG-Pal induced p70S6 kinase and JNK/CHOP signaling and promoted tubular injury. Fyn knockdown but not Lyn knockdown inhibited this detrimental signaling pathway. In addition, diabetic rats treated with KF-1607 showed improved kidney function and decreased ER stress, inflammation, and fibrosis compared with those treated with losartan. Collectively, these findings indicate that Fyn kinase is a specific member of the SFKs implicated in ER stress activation leading to proximal tubular injury in the diabetic milieu and that pan-SKI treatment attenuates kidney injury in diabetic rats. These data highlight Fyn kinase as a viable target for the development of therapeutic agents for DKD. Diabetes: A new approach to preventing kidney damage Insights into a signaling pathway that promotes diabetic kidney disease could lead to new therapies that protect against this major cause of kidney failure. Past studies have suggested that the various Src family kinase (SFK) signaling proteins play a part in the cell death and scar tissue formation associated with diabetic kidney disease. Hunjoo Ha of Ewha Womans University, Seoul, South Korea, and colleagues have now focused on one particular SFK, Fyn, as a direct driver of the kidney damage seen in mouse models of diabetes. Genetic interventions that selectively inhibit Fyn suppressed this damage, as did treatment with an oral drug that broadly inactivates SFKs. This experimental drug proved as effective as controlling inflammation and oxidative damage in the kidney as an already clinically approved treatment, confirming the significance of SFK signaling in this condition.