Nintedanib, a triple tyrosine kinase inhibitor, attenuates renal fibrosis in chronic kidney disease

Abstract

Nintedanib (BIBF1120) is a triple kinase inhibitor of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), vascular endothelial growth factor receptor (VEGFR), and Src family kinase, which has recently been approved by FDA to treat idiopathic pulmonary fibrosis. Whether it affects renal fibrosis remains unknown. Here, we demonstrated that administration of nintedanib immediately or 3 days after unilateral ureteral obstruction (UUO) injury and with folic acid (FA) injection attenuated renal fibrosis and inhibited activation of renal interstitial fibroblasts. Delayed administration of nintedanib also partially reversed established renal fibrosis. Treatment with nintedanib blocked UUO-induced phosphorylation of PDGFRβ, FGFR1, FGFR2, VEGFR2, and several Src family kinases including Src, Lck, Lyn as well as activation of signal transducer and activator of transcription-3 (STAT3), nuclear factor-κB (NF-κB), and Smad-3 in the kidney. Furthermore, nintedanib inhibited UUO-elicited renal proinflammatory cytokine expression and macrophage infiltration. These data indicate that nintedanib is a potent anti-fibrotic agent in the kidney and may hold therapeutic potential as a treatment of chronic fibrotic kidney disease.

A pericyte‐glia scarring develops at the leaky capillaries in the hippocampus during seizure activity

“…14 Inhibition of PDGFRβ signaling is proposed as a strategy to limit chronic inflammation and fibrosis. 18,20,21 Supporting this investigation, we previously reported PDGFRβ perivascular cell reactivity occurring in human brain specimens obtained from TLE with sclerosis, 8,24 a condition characterized by signs of neuroinflammation. 3,25 Finally, others have shown abnormal collagen IV immunoreactivity at the hippocampal microvascular network in human TLE.…”

“…The origin of PDGFRβ cells at the outer vascular wall is somehow controversial, either differentiating from a pericyte subtype or deriving from a specific resident population . Inhibition of PDGFRβ signaling is proposed as a strategy to limit chronic inflammation and fibrosis . Supporting this investigation, we previously reported PDGFRβ perivascular cell reactivity occurring in human brain specimens obtained from TLE with sclerosis, a condition characterized by signs of neuroinflammation .…”

“…Limiting fibrosis by targeting PDGFRβ signaling was proposed . Here, we show that imatinib was effective in reducing, in vitro, the ictal‐induced PDGFRβ reactivity.…”

“…PDGFRβ was recently reported as a biomarker of stromal cell activation, indicating fibrotic changes in peripheral and brain pathologies . Accumulating evidence indicates that perivascular PDGFRβ cells contribute to the buildup of fibrotic scar in lesions . The origin of PDGFRβ cells at the outer vascular wall is somehow controversial, either differentiating from a pericyte subtype or deriving from a specific resident population .…”

“…[14][15][16][17] Accumulating evidence indicates that perivascular PDGFRβ cells contribute to the buildup of fibrotic scar in lesions. [12][13][14][17][18][19][20][21] The origin of PDGFRβ cells at the outer vascular wall is somehow controversial, either differentiating from a pericyte subtype 17,22,23 or deriving from a specific resident population. 14 Inhibition of PDGFRβ signaling is proposed as a strategy to limit chronic inflammation and fibrosis.…”