Glucosidase Inhibitor Alleviates Inflammation and Fibrosis in Type‐1 Diabetic Kidney

Abstract

Diabetic nephropathy (DN) is characterized by renal fibrosis leading to chronic kidney disease and end‐stage renal disease. A plethora of evidence suggests that chronic inflammation plays a crucial role in the development of renal fibrosis, i.e., the accumulation of extracellular matrix (ECM) proteins in the glomerular and tubulointerstitial region. Moreover, epithelial‐mesenchymal transition (EMT), increased macrophage infiltration, elevated pro‐inflammatory cytokines and pro‐fibrotic factors contribute to renal fibrosis. Previous studies have shown that excess ECM accumulation leads to fibrosis in type‐1 diabetic kidney. Nimbidiol is a diterpenoid derived from the medicinal plant ‘neem’ (Azadirachta indica), and is reported to have anti‐diabetic properties by inhibiting glucosidases. Further, ‘neem’ extracts are shown to regulate oxidative stress, inflammation and ECM proteins in different disease models. The aim of our study was to understand the regulatory role of the glucosidase inhibitor, Nimbidiol on renal inflammation and fibrosis and its underlying signaling mechanisms in type‐1 DN. Wild type C57BL6/J (WT) and type‐1 diabetic C57BL6/‐Ins2Akita/J (Akita) mice (12‐14 weeks) were treated without or with Nimbidiol (0.4 mg/kg/day) for eight weeks. In diabetic kidney, the expression of CD40, the M1 macrophage marker, was elevated along with pro‐inflammatory cytokines viz., TNFα, IL‐6, IL‐1β and pro‐fibrotic factors including MCP‐1, TGF‐β1, α‐SMA and collagen. Additionally, Akita mice exhibited downregulation of CD206, the M2 macrophage marker and anti‐inflammatory cytokine, IL‐10 and also E‐cadherin in the kidney. The changes were associated with excess collagen deposition in the glomerular and tubulointerstitial region of the diabetic kidney compared to that of WT mice. Furthermore, the expression of NF‐κB, p‐Smad2/3, p‐P38, p‐JNK and p‐ERK were elevated in the diabetic kidney compared to the WT mice. Nimbidiol reversed the above changes to alleviate renal inflammation and fibrosis in Akita mice. Together, our results suggest that Nimbidiol protects the diabetic kidney from macrophage‐mediated inflammation and fibrosis by inhibiting NF‐κB, TGF‐β1/Smad and MAPK signaling pathways.