Tranilast prevents renal interstitial fibrosis by blocking mast cell infiltration in a rat model of diabetic kidney disease

Abstract

Renal interstitial fibrosis is a final pathway that is observed in various types of kidney diseases, including diabetic kidney disease (DKD). The present study investigated the effect of tranilast on renal interstitial fibrosis and the association between its role and mast cell infiltration in a rat model of DKD. A total of 30 healthy 6‑week‑old male Sprague‑Dawley rats were randomly divided into the following four groups: Normal control group; DKD model group; low‑dose tranilast group (200 mg/kg/day); and high‑dose tranilast group (400 mg/kg/day). The morphological alterations of tubulointerstitial fibrosis were evaluated by Masson's trichrome staining, while mast cell infiltration into the renal tubular interstitium was measured by toluidine blue staining and complement C3a receptor 1 (C3aR) immunohistochemical staining (IHC). The expression of fibronectin (FN), collagen I (Col‑I), stem cell factor (SCF) and proto‑oncogene c‑kit (c‑kit) was detected by IHC, western blotting and reverse transcription‑quantitative‑polymerase chain reaction. The results demonstrated that tubulointerstitial fibrosis and mast cell infiltration were observed in DKD model rats, and this was improved dose‑dependently in the tranilast treatment groups. The expression of FN, Col‑I, SCF and c‑kit mRNA and protein was upregulated in the tubulointerstitium of DKD model rats compared with the normal control rats, and tranilast inhibited the upregulated expression of these markers. Furthermore, the degree of SCF and c‑kit expression demonstrated a significant positive correlation with C3aR‑positive mast cells and the markers of renal interstitial fibrosis. The results of the present study indicate that mast cell infiltration may promote renal interstitial fibrosis via the SCF/c‑kit signaling pathway. Tranilast may prevent renal interstitial fibrosis through inhibition of mast cell infiltration mediated through the SCF/c-kit signaling pathway.

Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2−/− mice

“…PSC is characterized by hepatic fibrosis and our current study supports our previous work demonstrating that blocking MC infiltration and degranulation decreases liver fibrosis and HSC activation [11,14,15,17,18]. To support this, it has been shown that the SCF/c-Kit interaction promotes renal interstitial fibrosis [30]. Similar to our current findings, the authors found that, in a diabetic kidney disease model, the expression of fibronectin and collagen type-1a increases in diseased rats compared to normal and this was associated with increased SCF and c-Kit gene expression [30].…”

“…To support this, it has been shown that the SCF/c-Kit interaction promotes renal interstitial fibrosis [30]. Similar to our current findings, the authors found that, in a diabetic kidney disease model, the expression of fibronectin and collagen type-1a increases in diseased rats compared to normal and this was associated with increased SCF and c-Kit gene expression [30]. Additionally, following 70% partial hepatectomy, SCF levels increase over time and peak at 7 days [16].…”

Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury

“…Accumulation of B cells in the kidney can promote monocyte/macrophage recruitment by the secretion of CCL2, thus aggravating renal fibrosis. NK cells and C3aR + cells are also positively correlated with TIF, but the mechanisms involved remain unclear 105 , 106 .…”

Mast Cells in Diabetes and Diabetic Wound Healing

“…The release of such mediators from MCs may contribute to renal diseases and renal interstitial fibrosis and cause extracellular matrix (ECM) accumulation [53,54]. A recent study indicated that MC infiltration might promote renal interstitial fibrosis via the stem cell factor (SCF)/c-KIT signaling pathway, which can be inhibited by an antiallergic drug such as tranilast [55]. Another pathway in which MCs contribute to the pathogenesis of diabetic nephropathies might involve the renin-angiotensin system (RAS).…”