Abstract
Reduced glomerular filtration, hypertension and renal microvascular injury are hallmarks of chronic kidney disease, which has a global prevalence of ~10%. We have shown previously that the Fischer (F344) rat has lower GFR than the Lewis rat, and is more susceptible to renal injury induced by hypertension. In the early stages this injury is limited to the pre-glomerular vasculature. We hypothesized that poor renal hemodynamic function and vulnerability to vascular injury are causally linked and genetically determined. In the present study, normotensive F344 rats had a blunted pressure diuresis relationship, compared with Lewis rats. A kidney microarray was then interrogated using the Endeavour enrichment tool to rank candidate genes for impaired blood pressure control. Two novel candidate genes, P2rx7 and P2rx4, were identified, having a 7− and 3− fold increased expression in F344 rats. Immunohistochemistry localized P2X4 and P2X7 receptor expression to the endothelium of the pre-glomerular vasculature. Expression of both receptors was also found in the renal tubule; however there was no difference in expression profile between strains. Brilliant Blue G (BBG), a relatively selective P2X7 antagonist suitable for use in vivo, was administered to both rat strains. In Lewis rats, BBG had no effect on blood pressure, but increased renal vascular resistance, consistent with inhibition of some basal vasodilatory tone. In F344 rats BBG caused a significant reduction in blood pressure and a decrease in renal vascular resistance, suggesting that P2X7 receptor activation may enhance vasoconstrictor tone in this rat strain. BBG also reduced the pressure diuresis threshold in F344 rats, but did not alter its slope. These preliminary findings suggest a physiological and potential pathophysiological role for P2X7 in controlling renal and/or systemic vascular function, which could in turn affect susceptibility to hypertension-related kidney damage.
Highlights
Kidney injury and declining renal function are diagnostic indicators of kidney disease and present a global health burden with high population prevalence (Eckardt et al, 2013)
Compared to Lewis rats, F344 rats had a higher baseline blood pressure (Figure 1A) and a lower renal blood flow (Figure 1B): renal vascular resistance was significantly higher in F344 rats than in Lewis (Figure 1C)
We find that normotensive F344 rats have a blunted pressure diuresis relationship, which would impair blood pressure control and may underpin the susceptibility to vascular injury observed in this strain
Summary
Kidney injury and declining renal function are diagnostic indicators of kidney disease and present a global health burden with high population prevalence (Eckardt et al, 2013). Epigenetic and environmental factors determine susceptibility to renal injury and the development of chronic kidney disease. Hypertension is a major risk factor for kidney disease (Nakayama et al, 2011) and progression can be slowed if blood pressure is controlled (Hart and Bakris, 2010). Renal injury and fibrosis develop independently of barotrauma and the local actions of agents such as aldosterone (Ashek et al, 2012; Kawarazaki et al, 2012) and angiotensin II (Mori and Cowley, 2004; Polichnowski et al, 2011) have been implicated. We have previously used the Cyp1a1-Ren transgenic rat to investigate pathways leading to renal injury. In these rats, blood pressure is increased by dietary administration of the non-toxic aryl hydrocarbon, indole-3-carbinol (Kantachuvesiri et al, 2001). The rise in blood pressure can be titrated to study the organ injury associated with slowly developing (Conway et al, 2012)
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