Australia in 2030: what is our path to health for all?

CHAPTER 1: HOW AUSTRALIA IMPROVED HEALTH EQUITY THROUGH ACTION ON THE SOCIAL DETERMINANTS OF HEALTH: Do not think that the social determinants of health equity are old hat. In reality, Australia is very far away from addressing the societal level drivers of health inequity. There is little progressive policy that touches on the conditions of daily life that matter for health, and action to redress inequities in power, money and resources is almost non-existent. In this chapter we ask you to pause this reality and come on a fantastic journey where we envisage how COVID-19 was a great disruptor and accelerator of positive progressive action. We offer glimmers of what life could be like if there was committed and real policy action on the social determinants of health equity. It is vital that the health sector assists in convening the multisectoral stakeholders necessary to turn this fantasy into reality. CHAPTER 2: ABORIGINAL AND TORRES STRAIT ISLANDER CONNECTION TO CULTURE: BUILDING STRONGER INDIVIDUAL AND COLLECTIVE WELLBEING: Aboriginal and Torres Strait Islander peoples have long maintained that culture (ie, practising, maintaining and reclaiming it) is vital to good health and wellbeing. However, this knowledge and understanding has been dismissed or described as anecdotal or intangible by Western research methods and science. As a result, Aboriginal and Torres Strait Islander culture is a poorly acknowledged determinant of health and wellbeing, despite its significant role in shaping individuals, communities and societies. By extension, the cultural determinants of health have been poorly defined until recently. However, an increasing amount of scientific evidence supports what Aboriginal and Torres Strait Islander people have always said - that strong culture plays a significant and positive role in improved health and wellbeing. Owing to known gaps in knowledge, we aim to define the cultural determinants of health and describe their relationship with the social determinants of health, to provide a full understanding of Aboriginal and Torres Strait Islander wellbeing. We provide examples of evidence on cultural determinants of health and links to improved Aboriginal and Torres Strait Islander health and wellbeing. We also discuss future research directions that will enable a deeper understanding of the cultural determinants of health for Aboriginal and Torres Strait Islander people. CHAPTER 3: PHYSICAL DETERMINANTS OF HEALTH: HEALTHY, LIVEABLE AND SUSTAINABLE COMMUNITIES: Good city planning is essential for protecting and improving human and planetary health. Until recently, however, collaboration between city planners and the public health sector has languished. We review the evidence on the health benefits of good city planning and propose an agenda for public health advocacy relating to health-promoting city planning for all by 2030. Over the next 10 years, there is an urgent need for public health leaders to collaborate with city planners - to advocate for evidence-informed policy, and to evaluate the health effects of city planning efforts. Importantly, we need integrated planning across and between all levels of government and sectors, to create healthy, liveable and sustainable cities for all. CHAPTER 4: HEALTH PROMOTION IN THE ANTHROPOCENE: THE ECOLOGICAL DETERMINANTS OF HEALTH: Human health is inextricably linked to the health of the natural environment. In this chapter, we focus on ecological determinants of health, including the urgent and critical threats to the natural environment, and opportunities for health promotion arising from the human health co-benefits of actions to protect the health of the planet. We characterise ecological determinants in the Anthropocene and provide a sobering snapshot of planetary health science, particularly the momentous climate change health impacts in Australia. We highlight Australia's position as a major fossil fuel producer and exporter, and a country lacking cohesive and timely emissions reduction policy. We offer a roadmap for action, with four priority directions, and point to a scaffold of guiding approaches - planetary health, Indigenous people's knowledge systems, ecological economics, health co-benefits and climate-resilient development. Our situation requires a paradigm shift, and this demands a recalibration of health promotion education, research and practice in Australia over the coming decade. CHAPTER 5: DISRUPTING THE COMMERCIAL DETERMINANTS OF HEALTH: Our vision for 2030 is an Australian economy that promotes optimal human and planetary health for current and future generations. To achieve this, current patterns of corporate practice and consumption of harmful commodities and services need to change. In this chapter, we suggest ways forward for Australia, focusing on pragmatic actions that can be taken now to redress the power imbalances between corporations and Australian governments and citizens. We begin by exploring how the terms of health policy making must change to protect it from conflicted commercial interests. We also examine how marketing unhealthy products and services can be more effectively regulated, and how healthier business practices can be incentivised. Finally, we make recommendations on how various public health stakeholders can hold corporations to account, to ensure that people come before profits in a healthy and prosperous future Australia. CHAPTER 6: DIGITAL DETERMINANTS OF HEALTH: THE DIGITAL TRANSFORMATION: We live in an age of rapid and exponential technological change. Extraordinary digital advancements and the fusion of technologies, such as artificial intelligence, robotics, the Internet of Things and quantum computing constitute what is often referred to as the digital revolution or the Fourth Industrial Revolution (Industry 4.0). Reflections on the future of public health and health promotion require thorough consideration of the role of digital technologies and the systems they influence. Just how the digital revolution will unfold is unknown, but it is clear that advancements and integrations of technologies will fundamentally influence our health and wellbeing in the future. The public health response must be proactive, involving many stakeholders, and thoughtfully considered to ensure equitable and ethical applications and use. CHAPTER 7: GOVERNANCE FOR HEALTH AND EQUITY: A VISION FOR OUR FUTURE: Coronavirus disease 2019 has caused many people and communities to take stock on Australia's direction in relation to health, community, jobs, environmental sustainability, income and wealth. A desire for change is in the air. This chapter imagines how changes in the way we govern our lives and what we value as a society could solve many of the issues Australia is facing - most pressingly, the climate crisis and growing economic and health inequities. We present an imagined future for 2030 where governance structures are designed to ensure transparent and fair behaviour from those in power and to increase the involvement of citizens in these decisions, including a constitutional voice for Indigenous peoples. We imagine that these changes were made by measuring social progress in new ways, ensuring taxation for public good, enshrining human rights (including to health) in legislation, and protecting and encouraging an independent media. Measures to overcome the climate crisis were adopted and democratic processes introduced in the provision of housing, education and community development.

A mouse model of pseudohypoaldosteronism type II reveals a novel mechanism of renal tubular acidosis.

Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in ß-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.

Renal Mechanisms of Association between Fibroblast Growth Factor 1 and Blood Pressure.

The fibroblast growth factor 1 (FGF1) gene is expressed primarily in the kidney and may contribute to hypertension. However, the biologic mechanisms underlying the association between FGF1 and BP regulation remain unknown. We report that the major allele of FGF1 single nucleotide polymorphism rs152524 was associated in a dose-dependent manner with systolic BP (P = 9.65 × 10(-5)) and diastolic BP (P = 7.61 × 10(-3)) in a meta-analysis of 14,364 individuals and with renal expression of FGF1 mRNA in 126 human kidneys (P=9.0 × 10(-3)). Next-generation RNA sequencing revealed that upregulated renal expression of FGF1 or of each of the three FGF1 mRNA isoforms individually was associated with higher BP. FGF1-stratified coexpression analysis in two separate collections of human kidneys identified 126 FGF1 partner mRNAs, of which 71 and 63 showed at least nominal association with systolic and diastolic BP, respectively. Of those mRNAs, seven mRNAs in five genes (MME, PTPRO, REN, SLC12A3, and WNK1) had strong prior annotation to BP or hypertension. MME, which encodes an enzyme that degrades circulating natriuretic peptides, showed the strongest differential coexpression with FGF1 between hypertensive and normotensive kidneys. Furthermore, higher level of renal FGF1 expression was associated with lower circulating levels of atrial and brain natriuretic peptides. These findings indicate that FGF1 expression in the kidney is at least under partial genetic control and that renal expression of several FGF1 partner genes involved in the natriuretic peptide catabolism pathway, renin-angiotensin cascade, and sodium handling network may explain the association between FGF1 and BP.

Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension.

Inherited and acquired disorders that enhance the activity of transporters mediating renal tubular Na(+) reabsorption are well established causes of hypertension. It is unclear, however, whether primary activation of an Na(+)-independent chloride transporter in the kidney can also play a pathogenic role in this disease. Here, mice overexpressing the chloride transporter pendrin in intercalated cells of the distal nephron (Tg(B1-hPDS) mice) displayed increased renal absorption of chloride. Compared with normal mice, these transgenic mice exhibited a delayed increase in urinary NaCl and ultimately, developed hypertension when exposed to a high-salt diet. Administering the same sodium intake as NaHCO3 instead of NaCl did not significantly alter BP, indicating that the hypertension in the transgenic mice was chloride-sensitive. Moreover, excessive chloride absorption by pendrin drove parallel absorption of sodium through the epithelial sodium channel ENaC and the sodium-driven chloride/bicarbonate exchanger (Ndcbe), despite an appropriate downregulation of these sodium transporters in response to the expanded vascular volume and hypertension. In summary, chloride transport in the distal nephron can play a primary role in driving NaCl transport in this part of the kidney, and a primary abnormality in renal chloride transport can provoke arterial hypertension. Thus, we conclude that the chloride/bicarbonate exchanger pendrin plays a major role in controlling net NaCl absorption, thereby influencing BP under conditions of high salt intake.

Blood pressure regulation via the epithelial sodium channel: from gene to kidney and beyond.

The epithelial sodium channel (ENaC) has long been recognized as playing a vital role in blood pressure (BP) regulation due to its involvement in fluid balance. The genes encoding the three ENaC subunits are likewise important contributors to hypertension, both in rare monogenic diseases and in the general population. The unusually high numbers of genetic variants associated with complex traits, including BP, that are located in non-coding areas suggest an involvement of these variants in regulatory functions. This may involve differential regulation of expression in different tissues. Emerging evidence indicates that the ENaC plays an important role in BP determination not only via its actions in the kidney, but also in other tissues commonly involved in BP regulation. The ENaC in the central nervous system is proposed to regulate BP via sympathetic nervous system activity. Recent evidence suggests that the ENaC contributes to vascular function and the myogenic response. Additional roles potentially include initiation of the baroreceptor reflex via ENaC in the baroreceptors and driving high salt intake with a 'taste for salt' via ENaC in the tongue. The present review describes the involvement of the ENaC in the determination of BP at a genetic and physiological level, detailing recent evidence for its role in the kidney and in other pertinent tissues.

Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension.

Mutations in WNK1 and WNK4 lead to familial hyperkalemic hypertension (FHHt). Because FHHt associates net positive Na(+) balance together with K(+) and H(+) renal retention, the identification of WNK1 and WNK4 led to a new paradigm to explain how aldosterone can promote either Na(+) reabsorption or K(+) secretion in a hypovolemic or hyperkalemic state, respectively. WNK1 gives rise to L-WNK1, an ubiquitous kinase, and KS-WNK1, a kinase-defective isoform expressed in the distal convoluted tubule. By inactivating KS-WNK1 in mice, we show here that this isoform is an important regulator of sodium transport. KS-WNK1(-/-) mice display an increased activity of the Na-Cl cotransporter NCC, expressed specifically in the distal convoluted tubule, where it participates in the fine tuning of sodium reabsorption. Moreover, the expression of the ROMK and BKCa potassium channels was modified in KS-WNK1(-/-) mice, indicating that KS-WNK1 is also a regulator of potassium transport in the distal nephron. Finally, we provide an alternative model for FHHt. Previous studies suggested that the activation of NCC plays a central role in the development of hypertension and hyperkalemia. Even though the increase in NCC activity in KS-WNK1(-/-) mice was less pronounced than in mice overexpressing a mutant form of WNK4, our study suggests that the activation of Na-Cl cotransporter is not sufficient by itself to induce a hyperkalemic hypertension and that the deregulation of other channels, such as the Epithelial Na(+) channel (ENaC), is probably required.

Regulation of extracellular fluid volume and blood pressure by pendrin.

Na(+) is commonly designed as the culprit of salt-sensitive hypertension but several studies suggest that abnormal Cl(-) transport is in fact the triggering mechanism. This review focuses on the regulation of blood pressure (BP) by pendrin, an apical Cl(-)/HCO(3)(-) exchanger which mediates HCO(3)(-) secretion and transcellular Cl(-) transport in type B intercalated cells (B-ICs) of the distal nephron. Studies in mice showed that it is required not only for acid-base regulation but also for BP regulation as pendrin knock-out mice develop hypotension when submitted to NaCl restriction and are resistant to aldosterone-induced hypertension. Pendrin contributes to these processes by two mechanisms. First, pendrin-mediated Cl(-) transport is coupled with Na(+) reabsorption by the Na(+)-dependent Cl(-)/HCO(3)(-) exchanger NDCBE to mediate NaCl reabsorption in B-ICs. Second, pendrin activity regulates Na(+) reabsorption by the adjacent principal cells, possibly by interaction with the ATP-mediated paracrine signalling recently identified between ICs and principal cells. Interestingly, the water channel AQP5 was recently found to be expressed at the apical side of B-ICs, in the absence of a basolateral water channel, and pendrin and AQP5 membrane expressions are both inhibited by K(+) depletion, suggesting that pendrin and AQP5 could cooperate to regulate cell volume, a potent stimulus of ATP release.

Searching for functional genetic variants in non-coding DNA.

1. The search for DNA sequence variants for complex human polygenic conditions has been a strong focus of recent genetic research. While gene loci have been identified, few variants in the coding sequences of these genes have been found, suggesting that non-coding sequence variation may underlie many complex conditions. 2. Non-coding DNA harbours regulatory elements capable of making changes to gene expression. However, regulatory DNA sequences are currently difficult to recognize and their function is poorly understood, complicating the task of assigning potential functional significance to non-coding variation. 3. Comparative genomics, the study of evolutionary DNA conservation, has enabled the emergent field of non-coding DNA identification in human disease analysis. 4. This brief review will focus on the potential of a relatively high throughput technique based on comparative genomics, that may aid in the identification of functionally important non-coding sequence variation in complex diseases.

The epithelial sodium channel γ-subunit gene and blood pressure: family based association, renal gene expression, and physiological analyses.

Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

Selective genotyping reveals association between the epithelial sodium channel gamma-subunit and systolic blood pressure.

Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the gamma-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; n=96) and lower (mean: 98 mm Hg; n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P=0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10,000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (P=0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.