P930Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes (original) (raw)
Background: Brain natriuretic peptide (BNP) is an important biomarker for patients with cardiovascular diseases including heart failure and cardiac hypertrophy. It is known that BNP levels are relatively higher in patients with chronic kidney disease with no heart disease; however, its mechanism remains unclear. Purpose: Our purpose is to determine whether a substance in the renal papillary tip is associated with BNP or not. Methods: We developed a BNP reporter mouse, pBNP-tdTomato transgenic (Tg) mice, with the DNA fragments of mouse BNP 1.1k promoter into the expression vector of tdTomato and six lines of Tg mice were screened. To evaluate the activation of BNP promotor in aged mice, we examined the expression of tdTomato in each of organs from pBNP-tdTomato Tg mice. We attempted to establish a primary culture of the pBNP-tdTomato-positive cells from kidneys of BNP reporter mice. We investigated the effects of an extract of the papillary tip of rat on the expression of BNP in cultured rat neonatal cardiomyocytes with the use of northern blot and ELISA measurement. The blood pressure, serum BNP and urine cGMP were measured in stroke-prone spontaneous hypertensive rats (SHR-SP) after the extract from the papillary tip was injected intraperitoneally. Ligation of the rats' left anterior descending coronary artery was performed, and the effects of extracts from the papillary tips of kidneys of heart failure rats were examined five days after the induction of myocardial infarction. Results: In addition to the expression of tdTomato in cardiomyocytes, we occasionally found that the BNP promoter was activated specifically in the papillary tip of the kidneys and was not accompanied by BNP mRNA expression. pBNP-tdTomato-positive cells appeared to be interstitial and were not observed in any area of the kidneys except for the papillary tip. No evidence was observed to show the existence of BNP isoform or other nucleotide expression than BNP from around the BNP promotor region. Unexpectedly, both the expression and the secretion of BNP increased in the primary cultured neonatal cardiomyocytes after the treatment with the extract of the renal papillary tip. We were able to culture papillary tip tissue containing tdTomato-positive cells for more than 2 months, but no proliferation was observed. Intraperitoneal injection of the extract of the papillary tips reduced blood pressure accompanied by increasing serum BNP and urinary cGMP production in SHR-SP. Furthermore, the induction of BNP by the papillary extract from rats with heart failure due to myocardial infarction was increased in cardiomyocytes. Conclusions: These results suggest the interstitial cells in the renal papillary tip possess a substance that can stimulate BNP production and secretion from cardiomyocytes in vivo and in vitro.
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