Heart failure, or congestive heart failure, affects about 5.7 million people in the United States. The condition does not yet have a cure. Chronic kidney disease also impacts a large percentage of the U.S. population, with 14% being affected, and 47,000 cases resulting in death. Doctors closely link the two conditions in a phenomenon they call the cardiorenal syndrome — an umbrella term for several disorders that affect both the heart and kidneys. In cardiorenal syndrome, an acute or chronic dysfunction in one organ may trigger acute or chronic dysfunction in the other, and an increasing number of studies are trying to understand why. For instance, mounting evidence is showing that “the physiological communication between heart and kidney is necessary to maintain cardiovascular homeostasis,” and researchers have been using this lens to understand how chronic kidney disease raises the risk of heart failure. Other studies have looked at the role of the sympathetic nervous system, oxidative stress, inflammation, and the so-called renin-angiotensin system (RAS) in cardiorenal syndrome.
Biogenic amines are produced by the decarboxylation of amino acids and are delivered to tissues via blood circulation. All of them are also neuroactive: adrenaline, noradrenaline and dopamine play central roles in regulating sympathetic action, and this suggests that they may be implicated in the pathogenesis of cardiorenal damages. A role of serotonin in inducung heat fibrosis during CHF has been studied as well. As another member of the biogenic amines, histamine catalyzed by histidine decarboxylase (HDC) from histidine, plays a key role in the inflammatory response and is found to be elevated in patients with heart failure caused by acute myocardial infarction, by reperfusion injury, or by chronic kidney disease. Histamine is classically linked to allergic phenomena and vascular control in these contexts; there is almost no knowldge of its participating role in cardiovascular impairment seed in cardiorenal syndrome. Although this implies the involvement of increased histamine in the development of cardiac and renal dysfunctions, the significance and specific mechanism is entirely unknown.
Most of these studies have looked at cardiac and renal function separately, explain the authors of the latest research, as the number of animal models that can successfully replicate dysfunction in both systems at once is insufficient. Their study aims to fill this gap in research by creating an appropriate animal model. Akiyoshi Fukamizu, a professor at the University of Tsukuba in Japan, is the senior and corresponding author of the new paper. Using a mouse model, Prof. Fukamizu and his team have discovered an unexpected protective effect of histamine in cardiorenal syndrome. They have published their findings in the journal Proceedings of the National Academy of Sciences. Treating animals with the vasoconstrictive hormone angiotensin 2 (Ang II), has proven to affect blood pressure, as well as electrolyte and blood volume homeostasis. Some experts have suggested that Ang II may play a crucial role in the damage that occurs in cardiorenal syndrome. So, for this new study, Prof. Fukamizu and colleagues used the Ang II hormone to induce hypertension in mice, partial surgical removal of kidneys to induce kidney dysfunction, and salt to cause fluid retention.
Together, these interventions recreated the characteristics of cardiorenal syndrome in the rodents. The researchers found that in this animal model that they created in this specific way, blood plasma levels of histamine were high. They also found that this high concentration of histamine had a protective rather than a harmful effect on the heart and kidneys.To further test what was an intriguing finding, Histamine is an important factor in various inflammatory processes, and its inhibition generally leads to better disease control. The team went on to apply several substances that blocked various histamine receptors, until they found that blocking the histamine receptor H3 worsened cardiorenal damage. Specifically, the contractility of the heart was poorer, creatinine clearance — or the kidney’s ability to filter creatinine from the blood through urine — was also diminished, and the heart had increased in size in these mice. Further, the researchers gave the mice a histamine H3 agonist called immethridine, a substance that mimics the action of the natural histamine, and found that it protected against cardiorenal damage.
Additionally, immethridine treatment led to protective changes in gene expression that affected multiple genes linked to inflammation in these mice. The researchers hope that their findings will help bring new treatments for cardiorenal dysfunction in humans.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Noguchi K et al., Fukamizu A. PNAS USA 2020 Jan 28.
Hattori Y. Nihon Yakurigaku Zasshi 2018; 152(1):10-15.