The first point of our body’s contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions.

Future prospects continue to be strong for research using the rat as a model organism. New technology has enabled the proliferation of many new transgenic and knockout rat strains, the genomes of more than 40 rat strains have been sequenced, publications using the rat as a model continue to be produced at a steady rate, and discoveries of disease-associated genes and mechanisms from rat experiments abound, frequently with conservation of function between rats and humans. However, advances in genome technology have led to increasing insights into human disease directly from human genetic studies, pulling more and more researchers into the human genetics arena and placing funding for model organisms and their databases under threat. This, therefore, is a pivotal time for rat-based biomedical research – a timely moment to review progress and prospects – providing the inspiration for a new Special Collection focused on the impact of the model on translational science, launched in this issue of Disease Models & Mechanisms. What disease areas are most appropriate for research using rats? Why should the rat be favoured over other model organisms, and should the present levels of funding be continued? Which approaches should we expect to yield biologically and medically useful insights in the coming years? These are key issues that are addressed in the original Research Articles and reviews published in this Special Collection, and in this introductory Editorial. These exemplar articles serve as a landmark for the present status quo after a decade of major advances using the rat model and could help to guide the direction of rat research in the coming decade.

Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116±9 versus 154±25 mm Hg; urinary albumin excretion, 23±12 versus 170±80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational–lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats.

Significance: Zinc-finger nuclease (ZFN)-mediated mutagenesis has now enabled researchers to manipulate specific genes to test their function in animal models other than mice. Applying ZFNs to rats, we can now test the role of specific human genome-wide association studies (GWAS)-nominated genes for hypertension in a well-characterized hypertensive rat model, the Dahl salt-sensitive rat. This study provides the first functional evidence that the GWAS-nominated gene Plekha7 plays an essential role in blood pressure regulation and cardiovascular function by modulating vascular function. Our results indicate that Plekha7 plays a role in the regulation of intracellular calcium, nitric oxide bioavailability, and the response of the vasculature to increased flow.

Background: Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SS ^Per1−/− ), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure. Methods: The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm. Results: SS ^Per1−/− rats had similar mean arterial pressure when fed a normal 0.4% NaCl diet but developed augmented hypertension after three weeks on a high-salt (4% NaCl) diet. Despite being maintained on a normal 12:12 light:dark cycle, SS ^Per1−/− rats exhibited desynchrony mean arterial pressure rhythms on a high-salt diet, as evidenced by increased variability in the time of peak mean arterial pressure. SS ^Per1−/− rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SS ^Per1−/− rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SS ^Per1−/− rats also exhibited higher plasma aldosterone levels. Conclusions: Altogether, our findings demonstrate that loss of PER1 in Dahl SS rats causes an array of deleterious effects, including exacerbation of the development of salt-sensitive hypertension and renal damage.