Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat.

Abstract

Spontaneously hypertensive rats (SHR) and nonnotensive Wistar-Kyoto ("WKY") rats are frequently employed in experimental studies of hypertension. Although both SHR and WKY rat strains have been presumed to be fully inbred, recent studies have revealed important biologic variability in WKY rats from different commercial sources. Genealogk evidence suggests that, in the United States, breeding stocks of WKY rats may have been distributed to major commercial suppliers as early as the F10 generation. To test the hypothesis that commercially available WKY rats are genetically heterogeneous, we performed deoxyribonucleic acid (DNA) "fingerprint" analysis on genomic DNA of WKY rats from two of the largest vendors in the United States, Taconic Farms and Charles River Laboratories. We found molecular evidence of genetic variability not only among WKY rats from two different breeding facilities, but also among WKY rats within a single breeding facility (Taconic Farms). Although some studies have suggested the possibility of biologic variability in SHR from different sources, preliminary studies have not revealed molecular evidence of genetic heterogeneity in SHR from these vendors. In demonstrating genetic variability in WKY rats from different sources, the current study provides compelling evidence that rats designated WKY do not constitute an inbred strain. Accordingly, the results of studies in which SHR and WKY rats are compared might vary because of genetic heterogeneity in "the WKY rat control strain." (Hypertension 1989; 13:188-192) T he spontaneously hypertensive rat (SHR), initially bred in Kyoto, Japan, is the most widely studied experimental model of human essential hypertension. 12 Over the past 2 decades, numerous investigators have studied the pathogenesis of spontaneous hypertension by comparing SHR with normotensive Wistar-Kyoto rats (the so-called "WKY" strain) with respect to an enormous variety of physiological and biochemical characteristics. 2 Although both SHR and WKY rat strains have been presumed to be fully inbred, 3 recent studies have revealed important biologic

Selectively bred Wistar–Kyoto rats: an animal model of depression and hyper-responsiveness to antidepressants

“…19,20 However, genetic variability also exists within single vendor populations. 21,23 In the case of WKY/NHsd, this variability exists despite many generations of inbreeding. It is possible that heterogeneity in the strain is because of the development of new mutations.…”

“…Variability has been found in several behavioral and physiological measures 19,20 as well as genotypic heterogeneity between WKY rats obtained from different sources and within individual colonies. [21][22][23] Additionally, the responsiveness of WKY rats to antidepressants shows a wide range not found in other strains.…”

Elevated renovascular tone in young spontaneously hypertensive rats. Role of cytochrome P-450.

“…The renal vasculature of the Wistar-Lewis strain was studied to provide a second normotensive inbred control rat strain to compare with the SHR because of the evidence for genetic heterogeneity in the WKY rat 13 and its questionable adequacy as a control. The rats were anesthetized with pentobarbital (65 mg/kg body wt IP), and the left kidney was isolated and perfused for study of the juxtamedullary vasculature according to the method of Casellas and Navar 14 as modified by SanchezFerrer et al 15 The kidney was perfused with a cell-free physiological salt solution (PSS) containing (mmol/L) NaCl, 116; CaCl 2 , 2.5; KC1, 5; MgCl 2 , 0.76; NaH 2 CO 3 , 24; glucose, 11; HEPES, 5; and 5% bovine serum albumin, which was supplemented with a mixture of L-amino acids to support tubular function.…”

“…7 However, we felt it necessary to compare P-450 metabolism in young SHR, WKY, and WistarLewis rats because of the previously documented genetic differences in WKY rats obtained from different suppliers and questions regarding the adequacy of WKY rats as the sole normotensive control strain for SHR. 13 In addition, P-450 metabolism is dependent on age, sex, diet, and other environmental factors 17 ; there- fore, we felt it important to study P-450 metabolism of arachidonic acid in the same three groups of rats that were used in our renal microcirculatory studies. In these experiments, 3-to 4-week-old SHR, WKY, and WistarLewis rats were anesthetized with pentobarbital (65 mg/kg body wt IP).…”

Impaired reflex response to volume expansion in NaCl-sensitive spontaneously hypertensive rats.

“…Taconic Farms SHR and Charles River SHR were initially seeded 1 year apart from National Institutes of Health SHR stock at least 30 generations ago. SHR from these two sources show genetic homogeneity, 15 and the growth rate and time course for development of hypertension are similar for the two strains of SHR when maintained on normal NaCl diets. 16 Additionally, preliminary DNA fingerprinting of SHR from the colonies used in this study, carried out on DNA extracted by Dr. Allen Naftilan of our laboratories, showed no obvious genetic difference between SHR-S and SHR-R. 17 Therefore, differences in response to volume expansion would likely be related to differences in NaCl sensitivity, and use of the SHR-R as a NaCl-resistant control for the SHR-S strain would not be confounded by the different sources of the two strains.…”