Gene expression responses of threespine stickleback to salinity: implications for salt-sensitive hypertension

Abstract

Despite recent success with genome-wide association studies (GWAS), identifying hypertension (HTN)-susceptibility loci in the general population remains difficult. Here, we present a novel strategy to address this challenge by studying salinity adaptation in the threespine stickleback, a fish species with diverse salt-handling ecotypes. We acclimated native freshwater (FW) and anadromous saltwater (SW) threespine sticklebacks to fresh, brackish, and sea water for 30 days, and applied RNA sequencing to determine the gene expression in fish kidneys. We identified 1844 salt-responsive genes that were differentially expressed between FW sticklebacks acclimated to different salinities and/or between SW and FW sticklebacks acclimated to full-strength sea water. Significant overlap between stickleback salt-responsive genes and human genes implicated in HTN was detected (P < 10−7, hypergeometric test), suggesting a possible similarity in genetic mechanisms of salt handling between threespine sticklebacks and humans. The overlapping genes included a newly discovered HTN gene—MAP3K15, whose expression in FW stickleback kidneys decreases with salinity. These also included genes located in the GWAS loci such as AGTRAP-PLOD1 and CYP1A1-ULK3, which contain multiple potentially causative genes contributing to HTN susceptibility that need to be prioritized for study. Taken together, we show that stickleback salt-responsive genes provide valuable information facilitating the identification of human HTN genes. Thus, threespine sticklebacks may be used as a model, complementary to existing animal models, in human HTN research.

Kidney morphology and candidate gene expression shows plasticity in sticklebacks adapted to divergent osmotic environments

“…Active ion transport across plasma membranes; expressed in both gill and kidney tissues during osmoregulation (Perry et al, 2003;Wang et al, 2014). Outlier between freshwater and marine stickleback populations (DeFaveri et al, 2011;Shimada et al, 2011).…”

“…Freshwater osmoregulation -dilution of urine to conserve ions; expressed in kidney tubules (Kato et al, 2011;Wang et al, 2014).…”

“…These specific mechanisms have been studied in great detail in the gill (Evans et al, 1999(Evans et al, , 2005Hwang et al, 2011) and intestine (Lahlou, 1983;Grosell, 2006) of marine and freshwater fishes, and have revealed various degrees of plasticity in response to salinity transfer. However, the extent of associated cellular remodeling and/or transcriptional changes in the kidney has received less attention (but see Perry et al, 2003;Wang et al, 2014), especially in euryhaline species that can tolerate a wide range of salinities.…”

“…Moreover, whereas studies at the functional level have described transcriptional responses to salinity in both marine/anadromous and freshwater sticklebacks (McCairns and Bernatchez, 2010;Judd, 2012;Taugbøl et al, 2014;Divino et al, 2016), most have focused on gill rather than kidney tissue. Although a recent transcriptome-wide assay of salinity-induced changes in stickleback kidneys has provided a fresh insight into this important model system (Wang et al, 2014), its use of wild-caught test fish limits the ability to unambiguously discern genetically based divergence in expression from confounding environmental factors.…”

Interaction of the CYP1A1 gene polymorphism and smoking in non-small cell lung cancer susceptibility

“…However, the cytochrome P450 (CYP) 1A1 gene has not been studied extensively, and the results so far are confusing (Aldawsari et al, 2014;Wohak et al, 2014). Several studies (Lee et al, 2010;Arinc et al, 2014;Henderson et al, 2014;Wang et al, 2014;Gaspar-Ramirez et al, 2015) have shown that patients with CYP1A1 deletion cannot produce the active enzyme, so that carcinogenic substances cannot be metabolized and excreted. The long-term presence of carcinogenic substances coupled with smoking increased the susceptibility to lung cancer.…”