A new University of California, Irvine-led study reveals albumin (Alb), among the most abundant proteins in the body, activates a proton channel (hHv1), also widespread in the body, giving sperm the ability to penetrate and fertilize an egg, and allowing white blood cells to secrete large amounts of inflammatory mediators to fight infection.
The study titled “Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils,” was published today in Nature Communications.
Researchers examined the physiological connection between Alb and human voltage-gated proton channels (hHv1), which are both essential to cell biology in health and diseases. They also demonstrated the mechanism by which Alb binds directly to hHv1 to activate the channel.
This research explains how sperm are triggered to fertilize, and neutrophils are stimulated to release mediators in the innate immune response, describing a new role for Alb in physiology that will operate in the many tissues expressing hHv1.
“We found that the interaction of Alb and hHv1 activates sperm when they leave semen and enter the female reproductive tract because Alb is low in semen and high in the reproductive tract. We now understand why albumin supplementation improves IVF,” said first author Ruiming Zhao, Ph.D., from the Department of Physiology & Biophysics at UCI School of Medicine.
“We also found the same Alb/hHv1 interaction allows the white blood cells called neutrophils to produce and secrete the inflammatory mediators that kill bacteria and fight infection. However, it’s important to note that the inflammatory response itself can lead to disease.”
The essential stimulatory role of Alb in the physiology of sperm and neutrophils via hHv1 suggests that Alb will have as-yet unrecognized enhancing or deleterious roles in the other tissues, including the central nervous system, heart and lungs, and will influence cancers of the breast and gastrointestinal tract.
“It is exciting to discover that a common protein has the power to activate the proton channel. This finding suggests new strategies to block or enhance fertility, and to augment or suppress the innate immune response and inflammation,” said senior author Steve A. N. Goldstein, MD, Ph.D., vice chancellor of Health Affairs at UCI and distinguished professor in the School of Medicine Departments of Pediatrics and Physiology & Biophysics, and in the new School of Pharmacy and Pharmaceutical Sciences.
The proton channel hHv1 is implicated in a wide range of biological processes in addition to the capacitation of sperm and the innate immune responses included in the study. The channels have notable roles in proliferation of cancer cells, tissue damage during ischemic stroke, and hypertensive injury of the kidney.
Because Alb is ubiquitous at levels that vary in different human compartments in health and disease, the potentiation of hHv1 by Alb described in the paper will be widespread, tissue-dependent, and play both salutary and unfavorable roles in human physiology.
“We have modeled the structural basis for binding of Alb to the channel that leads to activation and changes in cellular function, and we are now conducting in vivo studies of viral and bacterial infections. Our next steps include studies of the effects of inhibitors of the Alb-hHv1 interaction on infection, inflammation and fertility,” said Goldstein.
The study was supported by the National Institutes of Health, US–Israel Binational Science Foundation, Universidad Nacional de Cuyo, Argentina, Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina, Universidad Nacional de Cuyo, Argentina, Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina, Universidad Nacional Autonoma de Mexico, Direccion General de Asuntos del Personal Academico, and Consejo Nacional de Ciencia y Tecnologia, Fronteras.
Infectious disease is one of the most important causes of morbidity and mortality among patients with end-stage renal disease (ESRD) [1,2,3]. According to the United States Renal Data System, infection is the second leading cause of death among patients with ESRD, and it comprises almost 9% of all deaths .
Similarly, almost 6000 hemodialysis patients in Japan die of infectious diseases annually, which amounts to approximately 20% of all-cause mortality of hemodialysis patients, and this rate is increasing every year [5, 6]. Given the high prevalence of infectious disease, early predictions of infection-related mortality could improve the outcome for hemodialysis patients.
Reports from previous studies have described diabetes, cancer, multisystem disease, vascular access type, serum albumin level, and being female as risk factors for infection-related mortality in patients who undergo renal replacement therapy [1, 7,8,9]. In this study, our focus was on serum albumin levels. Serum albumin is a known marker of nourishment, and it is also recognized as a marker of inflammation because it is an acute phase reactant [10,11,12].
Hypoalbuminemia in hemodialysis patients has been described as a risk factor for poor prognosis such as all-cause and cardiovascular-related mortality [8, 13,14,15,16,17]. However, infection-related mortality has been discussed in only two articles. Wang et al.  showed an association between serum albumin levels and bacteremia-related mortality, but did not discuss non-bacteremic infectious disease. Mehrotra et al.  discussed baseline and time-averaged serum albumin levels and changes in serum albumin levels, but they did not mention serum albumin levels at the onset of infectious disease.
In the general population, hypoalbuminemia has been described as a risk factor that is associated with poor clinical outcomes in acute illness , and it has been reported that the serum albumin level on admission is an independent risk factor associated with death, length of stay, and re-admission .
Although demonstrated in the general population, there has been insufficient evidence to support an association between hypoalbuminemia on admission and short-term mortality among hemodialysis patients who are usually more prone to develop hypoalbuminemia than the general population .
Therefore, we hypothesized that a low serum albumin level on admission is an important prognostic factor that is associated with short-term mortality, such as infection-related in-hospital death, among hemodialysis patients, as is the case within the general population. This study aimed to examine the influence of the serum albumin level on infection-related in-hospital death among chronic dialysis patients from whom blood cultures were obtained and who were hospitalized on suspicion of infectious disease.
reference link: https://rrtjournal.biomedcentral.com/articles/10.1186/s41100-018-0173-8
More information: Ruiming Zhao et al, Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils, Nature Communications (2021). DOI: 10.1038/s41467-021-24145-1