as-605240 and Fibrosis

Chronic kidney disease (CKD) poses a formidable challenge for public healthcare worldwide as vast majority of patients with CKD are also at risk of accelerated cardiovascular disease and death. Renal fibrosis is the common manifestation of CKD that usually leads to end-stage renal disease although the molecular events leading to chronic renal fibrosis and eventually chronic renal failure remain to be fully understood. Nonetheless, emerging evidence suggests that an aberrant activation of PI3Kγ signaling may play an important role in regulating profibrotic phenotypes. Here, we investigate whether a blockade of PI3Kγ signaling exerts any beneficial effect on alleviating kidney injury and renal fibrosis. Using a mouse model of angiotensin II (Ang II)-induced renal damage, we demonstrate that PI3Kγ inhibitor AS605240 effectively mitigates Ang II-induced increases in serum creatinine and blood urea nitrogen, renal interstitial collagen deposition, the accumulation of ECM proteins and the expression of α-Sma and fibrosis-related genes in vivo. Mechanistically, we reveal that AS605240 effectively inhibits Ang II-induced cell proliferation and phosphorylation of Akt in fibroblast cells. Furthermore, we demonstrate that Ang II-upregulated expression of IL-6, Tnf-α, IL-1β and Tgf-β1 is significantly attenuated in the mice treated with AS605240. Taken together, our results demonstrate that PI3Kγ may function as a critical mediator of Ang II-induced renal injury and fibrosis. It is thus conceivable that targeted inhibition of PI3Kγ signaling may constitute a novel therapeutic approach to the clinical management of renal fibrosis, renal hypertension and/or CKD.

Topics: Angiotensin II; Animals; Cell Proliferation; Class Ib Phosphatidylinositol 3-Kinase; Cytokines; Disease Models, Animal; Fibroblasts; Fibrosis; Kidney; Mice; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Quinoxalines; Renal Insufficiency, Chronic; Thiazolidinediones

To investigate the therapeutic effect of PI3Kgamma inhibitor AS605240 on cardiac hypertrophy and cardiac fibrosis induced by Isoproterenol in rats.. Wistar rats were randomly divided into three groups (n = 10), control group, ISO group (vehicle group) and AS605240 group. The rats in control group without any treatment. The rats in ISO and AS605240 group were given ISO 10 mg/kg for 3 days and 5 mg/kg for another 11 days by subcutaneous injection to prepare the animal model of cardiac fibrosis. Rats in AS605240 group were given AS605240 50 mg/(kg x d) by intraperitoneal injection continuously for 14 days. The vehicle group received the intraperitoneal injection of an equal volume of 0.5% carboxymethylcellulose. Twenty-four hours after the last treatment, rats were sacrificed. Heart, body weight, cardiac function and the CVF were measured.. Compared with the control group, the HW/BW of ISO group was increased significantly (P < 0.05) with a increased collagen inter cardiac muscle cells (P < 0. 05). Compared with ISO group, histological examination of the heart showed that AS605240 significantly relieved the rat cardiac fibrosis and reduced heart/body weight ratios in experimental cardiac fibrosis (P < 0.05).. AS605240 may be an effective antagonist for cardiac hypertrophy and cardiac fibrosis.

Topics: Animals; Cardiomegaly; Fibrosis; Isoproterenol; Male; Myocardium; Proteasome Endopeptidase Complex; Proteins; Quinoxalines; Random Allocation; Rats; Rats, Wistar; Thiazolidinediones