Repurposing a clinically approved prescription Colquhounia root tablet to treat diabetic kidney disease via suppressing PI3K/AKT/NF-kB activation

Abstract

Background: Growing clinical evidences show the potentials of Colquhounia root tablet (CRT) in alleviating diabetic kidney disease (DKD). However, its pharmacological properties and underlying mechanisms remain unclear. Methods: ‘Drug target-Disease gene’ interaction network was constructed and the candidate network targets were screened through evaluating node genes' topological importance. Then, a DKD rat model induced by high-fat diet/streptozotocin was established and used to determine pharmacological effects and network regulatory mechanisms of CRT against DKD, which were also verified using HK2 cell model induced by high glucose. Results: The candidate network targets of CRT against DKD were involved into various type II diabetes-related and nephropathy-related pathways. Due to the topological importance of the candidate network targets and the important role of the imbalance between immunity and inflammation in the pathogenesis of DKD, PI3K/AKT/NF-кB signaling-mediated immune-modulatory and anti-inflammatory actions of CRT were selected to be experimentally verified. On the basis of high-fat diet (HFD) / streptozotocin (STZ)-induced DKD rat model, CRT effectively reduced the elevated level of blood glucose, decreased the accumulation of renal lipid, suppressed inflammation and the generation of ECM proteins, and ameliorated kidney function and the renal histopathology through inhibiting the activation of PI3K, AKT and NF-кB proteins, reducing the nuclear accumulation of NF-кB protein and the serum levels of downstream cytokines, which were in line with the in vitro findings. Conclusions: Our data suggest that CRT may be the promising candidate drug for treating DKD via reversing the imbalance of immune-inflammation system mediated by the PI3K/AKT/NF-кB/IL-1β/TNF-α signaling.