ABSTRACT
Elevation of hypoxia-inducible factor 1 protein has been shown to be protective in acute kidney injury and HIF1α enhancing drug therapies are currently in clinical trials for the treatment of anemia of chronic kidney disease. Despite its benefits, long-term HIF1 elevation seems to be associated with additional effects in the kidneys such as tubulointerstitial fibrosis. To better understand the effects of prolonged HIF1 exposure, assessment of baseline and post-therapy levels of HIF1α and other related biomarkers is essential. In this study, we assessed the effect of HIF1α enhancement using prolyl hydroxylase inhibitor (PHD-I) DMOG, on a key profibrotic marker of kidney disease. In specific, we examined the change in expression of Collagen 4 subunit A2 in cultured urinary cells of CKD patients pre and post 24-hour exposure to 1mM DMOG. Our results show that besides HIF1α enhancement, COL4A2 protein is suppressed in presence of DMOG. To determine if this effect is mediated by HIF1, we used HIF1α gene silencing in HEK293 cells and examined the effect of DMOG on protein and gene expression of COL4A2 post 24-hour exposure. We showed that silencing HIF1α reverses and amplifies the expression of COL4A2 in HEK293 cells. Our data suggest that HIF1 directly regulates the expression of COL4A2 in kidney cells and that HIF1α enhancing therapy has suppressive effects on COL4A2 that may be clinically relevant and must be considered in determining the safety and efficacy of these drugs in the treatment of anemia.
Subject(s)
Amino Acids, Dicarboxylic/pharmacology , Collagen Type IV/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/drug effects , Prolyl-Hydroxylase Inhibitors/pharmacology , Renal Insufficiency, Chronic/metabolism , Urine/cytology , Aged , Aged, 80 and over , Anemia/drug therapy , Anemia/etiology , Collagen Type IV/genetics , Collagen Type IV/metabolism , Female , HEK293 Cells , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney Tubules/cytology , Male , Middle Aged , RNA Interference , Renal Insufficiency, Chronic/complicationsABSTRACT
The Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a randomized phase III trial that evaluated the outcomes of men with metastatic prostate cancer who received castration with or without docetaxel. Patients from this trial were genotyped in a recent study to detect HSD3B1 variance and to determine 2-y freedom from castration-resistant prostate cancer as well as overall survival. The results of this study identified HSD3B1 as a possible biomarker that can be used to predict response to therapy in patients with metastatic disease.
