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.

An Fgr kinase inhibitor attenuates sepsis-associated encephalopathy by ameliorating mitochondrial dysfunction, oxidative stress, and neuroinflammation via the SIRT1/PGC-1α signaling pathway

“…Src, Fyn, and Lyn have also been implicated in neuronal development, synaptic plasticity, and signal transduction [31][32][33]. In addition, Src, Fyn, Lck, Fgr, and Lyn have been associated with neurological disorders, including Alzheimer's disease, Parkinson's disease, pain, diabetes, and schizophrenia [29,30,[33][34][35][36]. However, to our knowledge, Fgr has not been reported to contribute to SAE.…”

Identification of endoplasmic reticulum stress-related biomarkers of diabetes nephropathy based on bioinformatics and machine learning

“…Importantly, the ER stress-mediated mechanism offers DN patients a possible treatment target. By inhibiting Fyn kinase-mediated ER stress, the Pan-Src kinase inhibitor described by Dorotea et al [34] reduces proximal tubular cell damage in a diabetic milieu. In addition, Zhong et al [35] discovered that dioscin protected against DN by decreasing oxidative stress, in ammation, and apoptosis caused by mitochondrial and ER stress.…”

Identification of endoplasmic reticulum stress-related biomarkers of diabetes nephropathy based on bioinformatics and machine learning

“…Importantly, the ER stress-mediated mechanism offers DN patients a possible treatment target. By inhibiting Fyn kinasemediated ER stress, the Pan-Src kinase inhibitor described by Dorotea et al (35) reduces proximal tubular cell damage in a diabetic milieu. In addition, Zhong et al (36) discovered that dioscin protected against DN by decreasing oxidative stress, inflammation, and apoptosis caused by mitochondrial and ER stress.…”