Abstract
Spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHRSP) are frequently used as models not only of essential hypertension and stroke, but also of attention-deficit hyperactivity disorder (ADHD). Normotensive Wistar-Kyoto (WKY) rats are normally used as controls in these studies. In the present study, we aimed to identify the genes causing hypertension and stroke, as well as the genes involved in ADHD using these rats. We previously analyzed gene expression profiles in the adrenal glands and brain. Since the kidneys can directly influence the functions of the cardiovascular, endocrine and sympathetic nervous systems, gene expression profiles in the kidneys of the 3 rat strains were examined using genome-wide microarray technology when the rats were 3 and 6 weeks old, a period in which rats are considered to be in a pre-hypertensive state. Gene expression profiles were compared between the SHRs and WKY rats and also between the SHRSP and SHRs. A total of 232 unique genes showing more than a 4-fold increase or less than a 4-fold decrease in expression were isolated as SHR- and SHRSP-specific genes. Candidate genes were then selected using two different web tools: the 1st tool was the Database for Annotation, Visualization and Integrated Discovery (DAVID), which was used to search for significantly enriched genes and categorized them using Gene Ontology (GO) terms, and the 2nd was Ingenuity Pathway Analysis (IPA), which was used to search for interactions among SHR- and also SHRSP-specific genes. The analyses of SHR-specific genes using IPA revealed that B-cell CLL/lymphoma 6 (Bcl6) and SRY (sex determining region Y)-box 2 (Sox2) were possible candidate genes responsible for causing hypertension in SHRs. Similar analyses of SHRSP-specific genes revealed that angiotensinogen (Agt), angiotensin II receptor-associated protein (Agtrap) and apolipoprotein H (Apoh) were possible candidate genes responsible for triggering strokes. Since our results revealed that SHRSP-specific genes isolated from the kidneys of rats at 6 weeks of age, included 6 genes related to Huntington's disease, we discussed the genetic association between ADHD and Huntington's disease.
Highlights
Studies have been conducted in an attempt to identify the genes causing hypertension using 2 strains of hypertensive rats: spontaneously hypertensive rats (SHRs) and a substrain derived from the SHRs, stroke-prone SHRs (SHRSP) [1,2]
Since we expected the expression of candidate genes to be regulated before elevations in blood pressure (BP), i.e., in the pre-hypertensive period, we examined the expression profiles of each probe using RNA samples prepared from the kidneys, and isolated a total of 353 SHR- and SHRSP-specific probes showing more than a 4-fold increase or less than a 4-fold decrease in expression (Table I)
Since our working hypothesis is that G-1 genes include genes that regulate the expression of G-2 genes, we examined the interactions between 69 G-1 and 96 G-2 genes using Ingenuity Pathway Analysis (IPA), and found 5 direct and 3 indirect interactions (Table I and Fig. 2): retinoid X receptor gamma (Rxrg) and group-specific component (Gc) interacted with cytochrome P450 subfamily 24 (Cyp24a1) [34,35]; B-cell CLL/lymphoma 6 (Bcl6) interacted with the following 3 genes: zinc finger and BTB domain containing 16 (Zbtb16) [9,10], protocadherin 9 (Pcdh9) [11] and Spi-B transcription factor (Spib) [12]; Cftr interacted with Ephx2 [36]; tumor protein p73 (Tp73) interacted with tetraspanin 1 (Tspan1) [37]; and Sox2 interacted with Tp73 [14]
Summary
Studies have been conducted in an attempt to identify the genes causing hypertension using 2 strains of hypertensive rats: spontaneously hypertensive rats (SHRs) and a substrain derived from the SHRs, stroke-prone SHRs (SHRSP) [1,2]. We investigated gene expression profiles in the adrenal glands [4], and subsequently in the brain [5]. Since the kidneys are logical candidate organs for studying hypertension due to their direct influence on body fluids and on the functions of the endocrine, cardiovascular and sympathetic nervous systems, in the present study, we aimed to investigate gene expression profiles in the kidneys. Since the association between kidney function and blood pressure is known to be influenced by numerous intrinsic and extrinsic factors, such as the renin‐angiotensin system and catecholamine and aldosterone hormones [6], we compared gene expression profiles in the kidneys of SHRs and WKY rats and between SHRSP and SHRs, when the rats were at 3 and 6 weeks old, a period in which rats are considered to be in a pre-hypertensive state. We isolated a total of 232 unique genes showing more than a 4-fold increase or less than a 4-fold decrease in expression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
