JTZ-951, a HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors.

JTZ-951, a HIF prolyl hydroxylase inhibitor, suppresses renal interstitial fibroblast transformation and expression of fibrosis-related factors. Am J Physiol Renal Physiol. 2019 Oct 21;: Authors: Wakashima T, Tanaka T, Fukui K, Komoda Y, Shinozaki Y, Kobayashi H, Matsuo A, Nangaku M Abstract Some preceding studies have provided evidence that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PH inhibitors) have therapeutic potential against tubular interstitial fibrosis (TIF). Recently, transformation of renal interstitial fibroblasts (RIFs) into alpha smooth muscle actin (αSMA)- positive myofibroblasts with loss of their hypoxia-inducible EPO expression has been hypothesized as the central mechanism responsible for TIF with renal anemia (the RIF hypothesis). These reports suggest that HIF-PH inhibitors may suppress TIF via suppressing transformation of RIFs. However, the direct effect of HIF-PH inhibitors on transformation of RIFs has not been demonstrated because there has been no appropriate assay system. Here, we established a novel in vitro model of the transformation of RIFs. This model expresses key phenotypic changes such as transformation of RIFs accompanied by loss of their hypoxia-inducible EPO expression, as proposed by the RIF hypothesis. Using this model, we demonstrated that JTZ-951, a newly developed HIF-PH inhibitor, stabilized HIF protein in RIFs, suppressed transformation of RIFs, and maintained their hyp...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research