Risk factors and mortality in dialysis patients with abdominal aortic aneurysm: A retrospective cohort study.

In the general population, abdominal aortic aneurysm (AAA) is synonymous with vascular disease and associated with increased mortality. Vascular disease is common in end-stage renal disease (ESRD) patients on dialysis, but there is limited information on AAA in this population. To address this issue, we queried the United States Renal Data System for risk factors associated with a diagnosis of AAA as well as the impact of AAA on ESRD patient survival. Incident dialysis patients from 2005 to 2014 with AAA and other clinical comorbidities were identified using ICD-9 and ICD-10 codes. Time to death was defined using the time from the start of dialysis to the date of death or to December 31, 2015. Cox proportional hazards (CPH) modeling was used to determine the adjusted hazard ratio (aHR) and 95% confidence intervals (CI) for death. From a total cohort of 820,826, we identified 21,631 subjects with a diagnosis of AAA. When compared to patients without AAA, AAA patients were older and more likely to be of white race and male gender, have a higher mean Charlson comorbidity index (CCI), have hypertension as the ESRD etiology, and use tobacco. Although a bivariate CPH model showed that AAA patients had an increased mortality risk compared to patients without the diagnosis, in the final CPH model, AAA patients had a decreased risk of mortality (aHR = 0.83, 95% CI 0.81-0.84) due to confounding with age. These results suggest that AAA is not associated with increased risk of death in ESRD patients after controlling for various demographic and clinical risk factors.

The Assessment of Infection Risk in Patients with Vitiligo Undergoing Dialysis for End-Stage Renal Disease: A Retrospective Cohort Study.

Vitiligo is an autoimmune condition that causes patchy skin depigmentation. Although the mechanism by which vitiligo induces immunocompromise is unclear, other related autoimmune diseases are known to predispose those affected to infection. Individuals with vitiligo exhibit epidermal barrier disruption, which could potentially increase their susceptibility to systemic infections; patients with renal disease also show a predisposition to infection. Nevertheless, there is little research addressing the risk of infection in dialysis patients with vitiligo in comparison to those without it. A retrospective analysis was performed on patients with end-stage renal disease (ESRD) in the United States Renal Data System who started dialysis between 2004 and 2019 to determine if ESRD patients with vitiligo are at an increased risk of bacteremia, cellulitis, conjunctivitis, herpes zoster, or septicemia. Multivariable logistic regression modeling indicated that female sex, black compared to white race, Hispanic ethnicity, hepatitis C infection, and tobacco use were associated with an enhanced risk of vitiligo, whereas increasing age and catheter, versus arteriovenous fistula, and access type were associated with a decreased risk. After controlling for demographics and clinical covariates, vitiligo was found to be significantly associated with an increased risk of bacteremia, cellulitis, and herpes zoster but not with conjunctivitis and septicemia.

Deep neck space infections in end-stage renal disease patients: Prevalence and mortality.

Deep neck space infections (DNSI) are severe infections within the layers of neck fascia that are known to be associated with underlying immunocompromised states. Although uremia associated with kidney disease is known to cause immune system dysfunction, DNSI in patients with kidney disease has been poorly studied. This study investigated the prevalence of DNSI and the associated risk of mortality within the United States end-stage renal disease (ESRD) population, using a retrospective cohort study design and the United States Renal Data System database of patients (ages 18-100) who initiated dialysis therapy between 2005 and 2019. International Classification of Disease-9 and -10 codes were used to identify the diagnosis of DNSI and comorbid conditions. Of the 705,891 included patients, 2.2% had a diagnosis of DNSI. Variables associated with increased risk of DNSI were female sex, black compared to white race, catheter, or graft compared to arteriovenous fistula (AVF) access, autoimmune disease, chronic tonsillitis, diagnoses in the Charlson Comorbidity Index (CCI), tobacco use, and alcohol dependence. DNSI diagnosis was an independent risk factor for mortality, which was also associated with other comorbidity factors such as older age, catheter or graft compared to AVF access, comorbidities in the CCI, tobacco use, and alcohol dependence. Because of the increased mortality risk of DSNI in the ESRD population, health professionals should encourage good oral hygiene practices and smoking cessation, and they should closely monitor these patients to reduce poor outcomes.

Risk factors and mortality in patients with listeriosis and end-stage renal disease.

BACKGROUND: End-stage renal disease (ESRD) is a known immunocompromising status that predisposes patients to developing infections. Disease from Listeria monocytogenes may affect any host but tends to be more severe in the immunocompromised. METHODS: We used a large population of patients with ESRD to identify risk factors for listeriosis and mortality. Patients with a diagnosis of Listeria and other risk factors for listeriosis were identified using claims data from the United States Renal Data System database from 2004-2015. Demographic parameters and risk factors associated with Listeria were modeled using logistic regression while association with mortality was assessed with Cox Proportional Hazards modeling. RESULTS: A diagnosis of Listeria was identified in 291 (0.01%) of a total 1,071,712 patients with ESRD. Cardiovascular disease, connective tissue disease, upper gastrointestinal ulcerative disease, liver disease, diabetes, cancer, and human immunodeficiency virus were all associated with an increased risk of Listeria. Patients with Listeria had an increased risk of death relative to patients without Listeria (adjusted hazard ratio=1.79; 95% confidence interval 1.52-2.10). CONCLUSIONS: Incidence of listeriosis in our study population was over 7 times higher than what has been reported for the general population. The independent association of a Listeria diagnosis with increased mortality is also consistent with the disease's high mortality in the general population. Due to limitations with diagnosis, providers should maintain high clinical suspicion for listeriosis when patients with ESRD present with a compatible clinical syndrome. Further prospective study may help precisely quantify the increased risk of listeriosis in patients with ESRD.

Sleep apnea in end-stage renal disease patients: risk factors and mortality.

Sleep apnea (SA) is highly prevalent in the end-stage renal disease (ESRD) population. However, the impact of SA on mortality in ESRD is unclear. This study investigates the relationship between SA and mortality in ESRD. The United States Renal Data System was queried in a retrospective cohort study to identify ESRD patients aged 18-100 years who initiated hemodialysis between 2005 and 2013. Diagnoses of SA and comorbidities were determined from International Classification of Disease-9 codes and demographic variables from Centers for Medicare and Medicaid Services Form-2728. Cox proportional hazards models were used to examine the association of SA with mortality controlling for multiple variables. Of 858,131 subjects meeting inclusion criteria, 587 were found to have central SA (CSA) and 22,724 obstructive SA (OSA). The SA cohort was younger and more likely to be male and Caucasian compared to the non-SA cohort, with more diagnoses of tobacco and alcohol use, hypertension, heart failure, and diabetes. Both CSA (adjusted hazard ratio (aHR) = 1.42, 95% confidence interval (CI): 1.29-1.56) and OSA (aHR = 1.35, 95% CI: 1.32-1.37) were associated with increased mortality. Other variables associated with increased mortality included age, dialysis initiation with a catheter or graft, alcohol use, hypertension, and cardiovascular disease. Factors associated with decreased mortality included female sex, black race, Hispanic ethnicity, diagnosis of heart failure or diabetes, and an ESRD etiology of glomerulonephritis or polycystic kidney disease. Since a diagnosis of either OSA or CSA increases mortality risk, early identification of SA and therapy in this ESRD population may improve survival.

Phospholipase D mediates very low-density lipoprotein-induced aldosterone production, in part, via lipin-1.

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of very low-density lipoprotein (VLDL). VLDL has been shown to induce aldosterone production in multiple adrenal zona glomerulosa models, mediated in part by phospholipase D (PLD). PLD is an enzyme that hydrolyzes phosphatidylcholine to produce phosphatidic acid (PA), a lipid second messenger that can also be dephosphorylated by lipin to yield diacylglycerol (DAG), yet another lipid signal. However, it is unclear which of the two lipid second messengers, PA or DAG, underlies PLD's mediation of aldosterone production. We hypothesized that the key signal produced by PLD (indirectly) is DAG such that PLD mediates VLDL-induced aldosterone production via lipin-mediated metabolism of PA to DAG. To assess the role of lipin in VLDL-induced aldosterone production, lipin-1 was overexpressed (using an adenovirus) or inhibited (using propranolol) in HAC15 cells followed by treatment with or without VLDL. Lipin-1 overexpression enhanced the VLDL-stimulated increase in CYP11B2 expression (by 75%), and lipin-1 inhibition decreased the VLDL-stimulated increase in CYP11B2 expression (by 66%). Similarly, the VLDL-stimulated increase in aldosterone production was enhanced by lipin-1 overexpression (182%) and was decreased by lipin inhibition (80%). Our results are suggestive of DAG being the key lipid signal since manipulating lipin-1 levels/activity affects VLDL-stimulated steroidogenic gene expression and ultimately, aldosterone production. Our study warrants further investigation into VLDL-stimulated steroidogenic signaling pathways which may lead to the identification of novel therapeutic targets, such as lipin-1 and its downstream pathways, to potentially treat obesity-associated hypertension.

Cutaneous squamous cell carcinoma and mortality in end-stage renal disease.

BACKGROUND: In the general population, cutaneous squamous cell carcinoma (cSCC) is associated with increased all-cause mortality. Transplant patients have been shown to have an increased risk of developing cSCC, and their cSCC is associated with an increased risk for mortality. In end-stage renal disease (ESRD) patients, there is extensive mortality and immune dysfunction. Because of this immune system dysfunction, we examined whether cSCC is associated with increased risk of all-cause mortality among ESRD patients, as well as the risk factors for cSCC. METHODS: We analyzed ESRD patients in the United States Renal Data System from 2004-2014, excluding organ transplant recipients. We assessed mortality using a Cox Proportional Hazards (CPH) model to control for various demographic and clinical parameters, identified using international classification of diseases (ICD)-9 codes. RESULTS: Of the 1,035,193 patients included, 624 (0.1%) were diagnosed with cSCC. The median survival time for those with cSCC was 3.91 years [95% confidence interval (CI) = 3.67-4.15], versus 2.92 years [95%CI = 2.92-2.93] for patients without cSCC. ESRD patients with cSCC were at lower risk of death [adjusted hazard ratio = 0.75; 95%CI = 0.69-0.82] compared to those without. Decreased risk of death was also associated with parameters such as black race, Hispanic ethnicity, tobacco dependence and actinic keratosis. Increased mortality risk was associated with increasing age, male sex, hemodialysis (versus peritoneal dialysis) and alcohol dependence. CONCLUSIONS: Contrary to expectations, ESRD patients with a cSCC diagnosis showed reduced all-cause mortality risk relative to those without. The reason for this discrepancy remains unclear, suggesting the need for further study.

Update on the Role of Glucocorticoid Signaling in Osteoblasts and Bone Marrow Adipocytes During Aging.

PURPOSE OF REVIEW: Bone marrow adipose tissue (BMAT) in the skeleton likely plays a variety of physiological and pathophysiological roles that are not yet fully understood. In elucidating the complex relationship between bone and BMAT, glucocorticoids (GCs) are positioned to play a key role, as they have been implicated in the differentiation of bone marrow mesenchymal stem cells (BMSCs) between osteogenic and adipogenic lineages. The purpose of this review is to illuminate aspects of both endogenous and exogenous GC signaling, including the influence of GC receptors, in mechanisms of bone aging including relationships to BMAT. RECENT FINDINGS: Harmful effects of GCs on bone mass involve several cellular pathways and events that can include BMSC differentiation bias toward adipogenesis and the influence of mature BMAT on bone remodeling through crosstalk. Interestingly, BMAT involvement remains poorly explored in GC-induced osteoporosis and warrants further investigation. This review provides an update on the current understanding of the role of glucocorticoids in the biology of osteoblasts and bone marrow adipocytes (BMAds).

Association of intermittent versus continuous hemodialysis modalities with mortality in the setting of acute stroke among patients with end-stage renal disease.

Patients with end-stage renal disease (ESRD) are 8-10 times more likely to suffer from a stroke compared with the general public. Despite this risk, there are minimal data elucidating which hemodialysis modality is best for patients with ESRD following a stroke, and guidelines for their management are lacking. We retrospectively queried the US Renal Data System administrative database for all-cause mortality in ESRD stroke patients who received either intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT). Acute ischemic stroke and hemorrhagic stroke were identified using the International Classification of Diseases 9th Revision (ICD-9)/ICD-10 codes, and hemodialysis modality was determined using Healthcare Common Procedure Coding System (HCPCS) codes. Time to death from the first stroke diagnosis was the outcome of interest. Cox proportional hazards modeling was used, and associations were expressed as adjusted HRs. From the inclusion cohort of 87,910 patients, 92.9% of patients received IHD while 7.1% of patients received CRRT. After controlling for age, race, sex, ethnicity, and common stroke risk factors such as hypertension, diabetes, tobacco use, atrial fibrillation, and hyperlipidemia, those who were placed on CRRT within 7 days of a stroke had an increased risk of death compared with those placed on IHD (HR=1.28, 95% CI 1.25 to 1.32). It is possible that ESRD stroke patients who received CRRT are more critically ill. However, even when the cohort was limited to only those patients in the intensive care unit and additional risk factors for mortality were controlled for, CRRT was still associated with an increased risk of death (HR=1.32, 95% CI 1.27 to 1.37). Therefore, further prospective clinical trials are warranted to address these findings.

Psoriasis and pneumonia in the end-stage renal disease population.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease associated with an increased risk for acute infections. Because chronic kidney disease is a risk factor for pneumonia, end-stage renal disease (ESRD) patients with psoriasis may have an increased risk for acquiring pneumonia. MATERIAL AND METHODS: A retrospective cohort analysis was performed using the United States Renal Data System, a medical claims database of all ESRD patients undergoing dialysis in the US. Logistic regression analysis was used to investigate the association of psoriasis with pneumonia in ESRD patients. RESULTS: A total of 6841 (0.7%) ESRD patients were diagnosed with psoriasis; 385,976 (36%) ESRD patients had pneumonia. Although simple models showed that psoriasis was associated with an increased risk of pneumonia in the ESRD population (odds ratio (OR) = 1.14), the final multivariable model found that psoriasis was protective for pneumonia (OR = 0.56) when controlling for age, race, sex, ethnicity, dialysis modality, Charlson Comorbidity Index (CCI), multiple sclerosis, tobacco use and alcohol use. This is due to both the CCI and tobacco use being strong confounders of the association of psoriasis and pneumonia. Black, other race and Hispanic ethnicity were also protective for pneumonia, while increasing age and CCI, female sex, hemodialysis, multiple sclerosis and tobacco and alcohol use were associated with increased risk. CONCLUSIONS: When controlling for multiple factors, psoriasis does not increase the risk for pneumonia in ESRD patients. In this cohort, other factors, such as the CCI and tobacco use, were more strongly associated with increased risk for pneumonia than psoriasis.

Development of Human Adrenocortical Adenoma (HAA1) Cell Line from Zona Reticularis.

The human adrenal cortex is composed of distinct zones that are the main source of steroid hormone production. The mechanism of adrenocortical cell differentiation into several functionally organized populations with distinctive identities remains poorly understood. Human adrenal disease has been difficult to study, in part due to the absence of cultured cell lines that faithfully represent adrenal cell precursors in the early stages of transformation. Here, Human Adrenocortical Adenoma (HAA1) cell line derived from a patient's macronodular adrenocortical hyperplasia and was treated with histone deacetylase inhibitors (HDACis) and gene expression was examined. We describe a patient-derived HAA1 cell line derived from the zona reticularis, the innermost zone of the adrenal cortex. The HAA1 cell line is unique in its ability to exit a latent state and respond with steroidogenic gene expression upon treatment with histone deacetylase inhibitors. The gene expression pattern of differentiated HAA1 cells partially recreates the roster of genes in the adrenal layer that they have been derived from. Gene ontology analysis of whole genome RNA-seq corroborated increased expression of steroidogenic genes upon HDAC inhibition. Surprisingly, HDACi treatment induced broad activation of the Tumor Necrosis Factor (TNF) alpha pathway. This novel cell line we developed will hopefully be instrumental in understanding the molecular and biochemical mechanisms controlling adrenocortical differentiation and steroidogenesis.

The Glucocorticoid Receptor in Osterix-Expressing Cells Regulates Bone Mass, Bone Marrow Adipose Tissue, and Systemic Metabolism in Female Mice During Aging.

Hallmarks of aging-associated osteoporosis include bone loss, bone marrow adipose tissue (BMAT) expansion, and impaired osteoblast function. Endogenous glucocorticoid levels increase with age, and elevated glucocorticoid signaling, associated with chronic stress and dysregulated metabolism, can have a deleterious effect on bone mass. Canonical glucocorticoid signaling through the glucocorticoid receptor (GR) was recently investigated as a mediator of osteoporosis during the stress of chronic caloric restriction. To address the role of the GR in an aging-associated osteoporotic phenotype, the current study utilized female GR conditional knockout (GR-CKO; GRfl/fl :Osx-Cre+) mice and control littermates on the C57BL/6 background aged to 21 months and studied in comparison to young (3- and 6-month-old) mice. GR deficiency in Osx-expressing cells led to low bone mass and BMAT accumulation that persisted with aging. Surprisingly, however, GR-CKO mice also exhibited alterations in muscle mass (reduced % lean mass and soleus fiber size), accompanied by reduced voluntary physical activity, and also exhibited higher whole-body metabolic rate and elevated blood pressure. Moreover, increased lipid storage was observed in GR-CKO osteoblastic cultures in a glucocorticoid-dependent fashion despite genetic deletion of the GR, and could be reversed via pharmacological inhibition of the mineralocorticoid receptor (MR). These findings provide evidence of a role for the GR (and possibly the MR) in facilitating healthy bone maintenance with aging in females. The effects of GR-deficient bone on whole-body physiology also demonstrate the importance of bone as an endocrine organ and suggest evidence for compensatory mechanisms that facilitate glucocorticoid signaling in the absence of osteoblastic GR function; these represent new avenues of research that may improve understanding of glucocorticoid signaling in bone toward the development of novel osteogenic agents. © 2021 American Society for Bone and Mineral Research (ASBMR).

Glycerol Improves Skin Lesion Development in the Imiquimod Mouse Model of Psoriasis: Experimental Confirmation of Anecdotal Reports from Patients with Psoriasis.

Glycerol is used in many skin care products because it improves skin function. Anecdotal reports by patients on the National Psoriasis Foundation website also suggest that glycerol may be helpful for the treatment of psoriasis, although to date no experimental data confirm this idea. Glycerol entry into epidermal keratinocytes is facilitated by aquaglyceroporins like aquaporin-3 (AQP3), and its conversion to phosphatidylglycerol, a lipid messenger that promotes keratinocyte differentiation, requires the lipid-metabolizing enzyme phospholipase-D2 (PLD2). To evaluate whether glycerol inhibits inflammation and psoriasiform lesion development in the imiquimod (IMQ)-induced mouse model of psoriasis, glycerol's effect on psoriasiform skin lesions was determined in IMQ-treated wild-type and PLD2 knockout mice, with glycerol provided either in drinking water or applied topically. Psoriasis area and severity index, ear thickness and ear biopsy weight, epidermal thickness, and inflammatory markers were quantified. Topical and oral glycerol ameliorated psoriasiform lesion development in wild-type mice. Topical glycerol appeared to act as an emollient to induce beneficial effects, since even in PLD2 knockout mice topical glycerol application improved skin lesions. In contrast, the beneficial effects of oral glycerol required PLD2, with no improvement in psoriasiform lesions observed in PLD2 knockout mice. Our findings suggest that the ability of oral glycerol to improve psoriasiform lesions requires its PLD2-mediated conversion to phosphatidylglycerol, consistent with our previous report that phosphatidylglycerol itself improves psoriasiform lesions in this model. Our data also support anecdotal evidence that glycerol can ameliorate psoriasis symptoms and therefore might be a useful therapy alone or in conjunction with other treatments.

Phenformin: AMP(K)ed for Potential Repurposing.

The results in the article by Zhou et al. (2020) demonstrate that the antidiabetic drug phenformin inhibits skin tumor growth and promotes keratinocyte differentiation, and an underlying mechanism is also defined. In this commentary, additional potential mechanisms through which phenformin may exert its antitumorigenic effect are described. Thus, the proposed repurposing of phenformin to treat skin cancer has merit.

Incidence and risk factors for HPV-associated cancers in women with end-stage renal disease.

Human papillomavirus (HPV) causes the majority of cervical, anal/rectal, and oropharyngeal cancers in women. End-stage renal disease (ESRD) is also associated with an increased risk of malignancy, but the incidence of and risk factors for HPV-associated cancers in US dialysis patients are not defined. We queried the US Renal Data System for women with HPV-associated cancers and assessed for incidence of cancer diagnosis and association of risk factors. From 2005 to 2011, a total of 1032 female patients with ESRD had 1040 HPV-associated cancer diagnoses. Patients had a mean age of 65 years, were mostly white (63%), and on hemodialysis (92%). Cervical cancer (54%) was the most common, followed by anal/rectal (34%), and oropharyngeal (12%). The incidence of HPV-associated cancers in patients with ESRD increased yearly, with up to a 16-fold increased incidence compared with the general population. Major risk factors associated with the development of any HPV-associated cancer included smoking (adjusted relative risk=1.89), alcohol use (1.87), HIV (2.21), and herpes infection (2.02). Smoking, HIV, and herpes infection were prominent risk factors for cervical cancer. The incidence of HPV-associated cancers in women with ESRD is rising annually and is overall higher than in women of the general population. Tobacco use is a universal risk factor. For cervical cancer, the presence of HIV and herpes are important comorbidities. Recognizing risk factors associated with these cancers may improve diagnosis and facilitate survival. The role of HPV vaccination in at-risk dialysis patients remains to be defined but warrants further study.

Age-related increase of kynurenine enhances miR29b-1-5p to decrease both CXCL12 signaling and the epigenetic enzyme Hdac3 in bone marrow stromal cells.

Mechanisms leading to age-related reductions in bone formation and subsequent osteoporosis are still incompletely understood. We recently demonstrated that kynurenine (KYN), a tryptophan metabolite, accumulates in serum of aged mice and induces bone loss. Here, we report on novel mechanisms underlying KYN's detrimental effect on bone aging. We show that KYN is increased with aging in murine bone marrow mesenchymal stem cells (BMSCs). KYN reduces bone formation via modulating levels of CXCL12 and its receptors as well as histone deacetylase 3 (Hdac3). BMSCs responded to KYN by significantly decreasing mRNA expression levels of CXCL12 and its cognate receptors, CXCR4 and ACKR3, as well as downregulating osteogenic gene RUNX2 expression, resulting in a significant inhibition in BMSCs osteogenic differentiation. KYN's effects on these targets occur by increasing regulatory miRNAs that target osteogenesis, specifically miR29b-1-5p. Thus, KYN significantly upregulated the anti-osteogenic miRNA miR29b-1-5p in BMSCs, mimicking the up-regulation of miR-29b-1-5p in human and murine BMSCs with age. Direct inhibition of miR29b-1-5p by antagomirs rescued CXCL12 protein levels downregulated by KYN, while a miR29b-1-5p mimic further decreased CXCL12 levels. KYN also significantly downregulated mRNA levels of Hdac3, a target of miR-29b-1-5p, as well as its cofactor NCoR1. KYN is a ligand for the aryl hydrocarbon receptor (AhR). We hypothesized that AhR mediates KYN's effects in BMSCs. Indeed, AhR inhibitors (CH-223191 and 3',4'-dimethoxyflavone [DMF]) partially rescued secreted CXCL12 protein levels in BMSCs treated with KYN. Importantly, we found that treatment with CXCL12, or transfection with an miR29b-1-5p antagomir, downregulated the AhR mRNA level, while transfection with miR29b-1-5p mimic significantly upregulated its level. Further, CXCL12 treatment downregulated IDO, an enzyme responsible for generating KYN. Our findings reveal novel molecular pathways involved in KYN's age-associated effects in the bone microenvironment that may be useful translational targets for treating osteoporosis.

Aquaporin-3 in the epidermis: more than skin deep.

The skin is essential for terrestrial life. It is responsible for regulating water permeability and functions as a mechanical barrier that protects against environmental insults such as microbial infection, ultraviolet light, injury, and heat and cold, which could damage the cells of the body and compromise survival of the organism. This barrier is provided by the outer layer, the epidermis, which is composed predominantly of keratinocytes; keratinocytes undergo a program of differentiation to form the stratum corneum comprising the cornified squame "bricks" and lipid "mortar." Dysregulation of this differentiation program can result in skin diseases, including psoriasis and nonmelanoma skin cancers, among others. Accumulating evidence in the literature indicates that the water-, glycerol-, and hydrogen peroxide-transporting channel aquaporin-3 (AQP3) plays a key role in various processes involved in keratinocyte function, and abnormalities in this channel have been observed in several human skin diseases. Here, we discuss the data linking AQP3 to keratinocyte proliferation, migration, differentiation, and survival as well as its role in skin properties and functions like hydration, water retention, wound healing, and barrier repair. We also discuss the mechanisms regulating AQP3 levels, localization, and function and the anomalies in AQP3 that are associated with various skin diseases.

Pathogen-Associated Molecular Pattern-Induced TLR2 and TLR4 Activation Increases Keratinocyte Production of Inflammatory Mediators and is Inhibited by Phosphatidylglycerol.

Skin serves not only as a protective barrier to microbial entry into the body but also as an immune organ. The outer layer, the epidermis, is composed predominantly of keratinocytes, which can be stimulated to produce proinflammatory mediators. Although some inflammation is useful to defend against infection, excessive or persistent inflammation can lead to the development of inflammatory skin diseases, such as psoriasis, a common skin disorder affecting approximately 2% of the US population. We have previously found that phosphatidylglycerol (PG) derived from soy can inhibit inflammation in a contact irritant ear edema mouse model. Here, we investigated the ability of soy PG to inhibit inflammatory mediator expression in response to activators of the pattern recognition receptors, toll-like receptor-2 (TLR2) and -4 (TLR4). We found that in epidermal keratinocytes, soy PG inhibited TLR2 and TLR4 activation and inflammatory mediator expression in response to a synthetic triacylated lipopeptide and lipopolysaccharide, respectively, as well as an endogenous danger-associated molecular pattern. However, at higher concentrations, soy PG alone enhanced the expression of some proinflammatory cytokines, suggesting a narrow therapeutic window for this lipid. Dioleoylphosphatidylglycerol (DOPG), but not dioleoylphosphatidylcholine, exerted a similar inhibitory effect, completely blocking keratinocyte inflammatory mediator expression induced by TLR2 and TLR4 activators as well as NFκB activation in a macrophage cell line (RAW264.7); however, DOPG was not itself proinflammatory even at high concentrations. Furthermore, DOPG had no effect on NFκB activation in response to a TLR7/8 agonist. Our results suggest that DOPG could be used to inhibit excessive skin inflammation. SIGNIFICANCE STATEMENT: Although inflammation is beneficial for clearing an infection, in some cases, the infection can be excessive and/or become chronic, thereby resulting in considerable tissue damage and pathological conditions. We show here that the phospholipid phosphatidylglycerol can inhibit the activation of toll-like receptors 2 and 4 of the innate immune system as well as the downstream inflammatory mediator expression in response to microbial component-mimicking agents in epidermal keratinocytes that form the physical barrier of the skin.

Keratinocyte aquaporin-3 expression induced by histone deacetylase inhibitors is mediated in part by peroxisome proliferator-activated receptors (PPARs).

The water and glycerol channel, aquaporin-3 (AQP3), plays an important role in the skin epidermis, with effects on hydration, permeability barrier repair and wound healing; therefore, information about the mechanisms regulating its expression is important for a complete understanding of skin function physiologically and in disease conditions. We previously demonstrated that histone deacetylase inhibitors (HDACi) induce the mRNA and protein expression of AQP3, in part through the p53 family, transcription factors for which acetylation is known to affect their regulatory activity. Another set of transcription factors previously shown to induce AQP3 expression and/or regulate skin function are the peroxisome proliferator-activated receptors (PPARs). Since there are reports that PPARs are also acetylated, we examined the involvement of these nuclear hormone receptors in HDACi-induced AQP3 expression. We first verified that a PPARγ agonist upregulated AQP3 mRNA and protein levels and that this increase was blocked by a PPARγ antagonist. We then showed that the PPARγ antagonist also inhibited AQP3 expression induced both by a broad-spectrum HDACi and an HDAC3-selective inhibitor. Interestingly, a PPARα antagonist also inhibited HDACi-induced AQP3 expression. These antagonist effects were observed in both primary mouse and normal human keratinocytes. Furthermore, PPARγ overexpression enhanced HDACi-stimulated AQP3 mRNA levels. Thus, our results suggest that PPARγ and/or PPARα may play a role in regulating AQP3 levels in the skin; based on the ability of PPAR agonists to promote epidermal differentiation and/or inhibit proliferation, topical PPAR agonists might be considered as a therapy for hyperproliferative skin disorders, such as psoriasis.

Picolinic acid, a tryptophan oxidation product, does not impact bone mineral density but increases marrow adiposity.

Tryptophan is an essential amino acid catabolized initially to kynurenine (kyn), an immunomodulatory metabolite that we have previously shown to promote bone loss. Kyn levels increase with aging and have also been associated with neurodegenerative disorders. Picolinic acid (PA) is another tryptophan metabolite downstream of kyn. However, in contrast to kyn, PA is reported to be neuroprotective and further, to promote osteogenesis in vitro. Thus, we hypothesized that PA might be osteoprotective in vivo. In an IACUC-approved protocol, we fed PA to aged (23-month-old) C57BL/6 mice for eight weeks. In an effort to determine potential interactions of PA with dietary protein we also fed PA in a low-protein diet (8%). The mice were divided into four groups: Control (18% dietary protein), +PA (700 ppm); Low-protein (8%), +PA (700 ppm). The PA feedings had no impact on mouse weight, body composition or bone density. At sacrifice bone and stem cells were collected for analysis, including µCT and RT-qPCR. Addition of PA to the diet had no impact on trabecular bone parameters. However, marrow adiposity was significantly increased in PA-fed mice, and in bone marrow stromal cells isolated from these mice increases in the expression of the lipid storage genes, Plin1 and Cidec, were observed. Thus, as a downstream metabolite of kyn, PA no longer showed kyn's detrimental effects on bone but instead appears to impact energy balance.