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Abstract Polycystic kidney diseases (PKD) are genetic disorders which disrupt kidney architecture and function. Autosomal recessive PKD (ARPKD) is a rare form of PKD, caused by mutations in PKHD1, and clinically more severe than the more common autosomal dominant PKD (ADPKD). Prior studies have implicated Hedgehog (Hh) signaling in ADPKD, with increased levels of Hh components in experimental ADPKD and reduced cystogenesis following pharmacological Hh inhibition. In contrast, the role of the Hh pathway in ARPKD is poorly understood. We hypothesized that Hh pathway activity would be elevated during ARPKD pathogenesis, and its modulation may slow disease progression. We utilized Cpk mice which phenocopy ARPKD and generated a PKHD1‐mutant spheroid model in human collecting ducts. Significantly elevated levels of the Hh transcriptional effector Gli3 were found in Cpk mice, a finding replicated in PKHD1‐mutant spheroids. In Cpk mice, total GLI3 and GLI3 repressor protein levels were also increased. Reduction of increased Gli3 levels via heterozygous genetic deletion in Cpk mice did not affect cyst formation. Additionally, lowering GLI3 transcripts to wildtype levels did not influence PKHD1‐mutant spheroid size. Collectively, these data suggest attenuation of elevated Gli3 does not modulate murine and human models of ARPKD.

Abstract Cardiotrophin‐1 (CT‐1), a member of the interleukin (IL)‐6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT‐1 also has a protective role in immune‐mediated glomerular disease. Using immunohistochemistry and analysis of single‐cell RNA‐sequencing data of isolated glomeruli, we demonstrate that CT‐1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT‐1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT‐1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT‐1 treatment also reduced fibrosis in the kidney cortex, peri‐glomerular macrophage accumulation and the kidney levels of the pro‐inflammatory mediator complement component 5a. In conclusion, CT‐1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.

Abstract The development of vascular networks in microfluidic chips is crucial for the long-term culture of three-dimensional cell aggregates such as spheroids, organoids, tumoroids, or tissue explants. Despite rapid advancement in microvascular network systems and organoid technologies, vascularizing organoids-on-chips remains a challenge in tissue engineering. Most existing microfluidic devices poorly reflect the complexity of in vivo flows and require complex technical set-ups. Considering these constraints, we develop a platform to establish and monitor the formation of endothelial networks around mesenchymal and pancreatic islet spheroids, as well as blood vessel organoids generated from pluripotent stem cells, cultured for up to 30 days on-chip. We show that these networks establish functional connections with the endothelium-rich spheroids and vascular organoids, as they successfully provide intravascular perfusion to these structures. We find that organoid growth, maturation, and function are enhanced when cultured on-chip using our vascularization method. This microphysiological system represents a viable organ-on-chip model to vascularize diverse biological 3D tissues and sets the stage to establish organoid perfusions using advanced microfluidics.

Abstract Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease.

Abstract Diabetes mellitus (DM) is the leading cause of chronic kidney disease and diabetic nephropathy is widely studied. In contrast, the pathobiology of diabetic urinary bladder disease is less understood despite dysfunctional voiding being common in DM. We hypothesised that diabetic cystopathy has a characteristic molecular signature. We therefore studied bladders of hyperglycaemic and polyuric rats with streptozotocin (STZ)-induced DM. Sixteen weeks after induction of DM, as assessed by RNA arrays, wide-ranging changes of gene expression occurred in DM bladders over and above those induced in bladders of non-hyperglycaemic rats with sucrose-induced polyuria. The altered transcripts included those coding for extracellular matrix regulators and neural molecules. Changes in key genes deregulated in DM rat bladders were also detected in db/db mouse bladders. In DM rat bladders there was reduced birefringent collagen between detrusor muscle bundles, and atomic force microscopy showed a significant reduction in tissue stiffness; neither change was found in bladders of sucrose-treated rats. Thus, altered extracellular matrix with reduced tissue rigidity may contribute to voiding dysfunction in people with long-term DM. These results serve as an informative stepping stone towards understanding the complex pathobiology of diabetic cystopathy.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

The orientation of cells in two-dimensional and three-dimensional space underpins how the kidney develops and responds to disease. The process by which cells orientate themselves within the plane of a tissue is termed planar cell polarity. In this Review, we discuss how planar cell polarity and the proteins that underpin it govern kidney organogenesis and pathology. The importance of planar cell polarity and its constituent proteins in multiple facets of kidney development is emphasised, including ureteric bud branching, tubular morphogenesis and nephron maturation. An overview is given of the relevance of planar cell polarity and its proteins for inherited human renal diseases, including congenital malformations with unknown aetiology and polycystic kidney disease. Finally, recent work is described outlining the influence of planar cell polarity proteins on glomerular diseases and highlight how this fundamental pathway could yield a new treatment paradigm for nephrology.

Summary: The authors hypothesized that despite similar cardiovascular event rates, the improved cardiovascular survival from sodium glucose transporter 2 (SGLT2) inhibition, seen clinically, could be via a direct cytoprotective effect, including protection against myocardial ischemia/reperfusion injury. Langendorff-perfused hearts, from diabetic and nondiabetic rats, fed long-term for 4 weeks with canagliflozin, had lower infarct sizes; this being the first demonstration of canagliflozin’s cardioprotective effect against ischemia/reperfusion injury in both diabetic and nondiabetic animals. By contrast, direct treatment of isolated nondiabetic rat hearts with canagliflozin, solubilized in the isolated Langendorff perfusion buffer, had no impact on infarct size. This latter study demonstrates that the infarct-sparing effect of long-term treatment with canagliflozin results from either a glucose-independent effect or up-regulation of cardiac prosurvival pathways. These results further suggest that SGLT2 inhibitors could be repurposed as novel cardioprotective interventions in high-risk cardiovascular patients irrespective of diabetic status. Key Words: cardioprotection, diabetes, ischemia-reperfusion injury, myocardial infarction, SGLT2 inhibitor

Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising. The planar cell polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly because of the perinatal lethality of many PCP mouse mutant lines. Here, we investigate heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage, including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in emphysema. In vitro, disruption of VANGL2 impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking on lung function. Finally, we show that PCP genes VANGL2 and SCRIB are significantly downregulated in lung tissue from patients with emphysema. Our data reveal an important novel role for the PCP pathway in adult lung homeostasis and repair and shed new light on the genetic factors which may modify destructive lung diseases such as emphysema.

What is the future of environmental and climate change education in the United States given the emergence of neofascist and Christian Nationalist political movements during a time of social secularization? In this essay we discuss the politically heterogenous appeal of environmental concern in America, the tenuous nature of environmental education's current Left-liberal political valence, and implications for climate change education amidst ongoing culture wars. We proceed by examining Bron Taylor's influential typology of Dark Green Religions and consider how the American political Right may emerge as having their own Dark Green Religious movement. We are concerned that the field of environmental education remains ideologically blinkered toward other normative educational projects on the political Right, a situation that leaves us unprepared for how projects such as climate change education can be appropriated for reactionary and sometimes violent ends. We argue that the field of environmental education needs to pay greater attention to the multifarious political and cultural conditions that shape its enactment and develop considerations for an anti-fascist environmental education accordingly.

Discussions about the status of scholarly journals in management have tended to revolve around impact factor and standing on relevant lists-cues whose validity has been oft-debated. We introduce a new metric for gauging the status of scholarly journals. Syllabus share represents the proportion of doctoral seminar syllabi comprised of articles from a given journal. We introduce this metric by drawing on a content analysis of 179 management doctoral syllabi (90 micro seminars, 89 macro seminars) from 53 business schools in North America, Europe, and Asia. Our results showed that syllabus share was distinct from impact factor and standing on relevant ranking and advisory lists. Moreover, syllabus share was correlated with perceptions of journal status on the part of both junior and senior scholars. Syllabus share provides a more continuous view of journal status (in contrast to lists) while allowing results to be contextualized (in contrast to impact factor). Our discussion focuses on the value of syllabus share for a more pluralistic conceptualization of journal status and its contributions to the scholarship of management education.

This Forum article extends themes and critical observations within Jenna Scaramanga and Michael Reiss's article "Evolutionary Stasis: Creationism, Evolution and Climate Change in the Accelerated Christian Education curriculum," published in "CSSE." The Accelerated Christian Education curriculum is a package of homeschool units and lesson designed to underscore and support conservative Christian students, teachers, and/or parents in their mission to align their students unfolding understanding of the world within the strict cognitive bounds of fundamentalist Christianity. Within this curriculum, both evolution and climate change are presented as unreasonable and/or silly against the purported superior evidence of the inerrant ontology of (their extremely narrow interpretation of the) the Bible. Scaramanga and Reiss's analysis frame this kind of understanding within fundamentalist Christianity as indicative of a conspiracy theory. This article extends, questions, and suggests reframing these rhetorical moves toward a more robust and straightforward question of conservative Christianity as a player within a political economy. I suggest we take such groups more seriously for their highly effective if to some perspectives silly interpretation of Biblical text. For many, this movement is simply the maintenance of white male patriarchal power via religious identity. Implications, given the ease of movement of such texts in our digital age, are drawn for the use of such curricula in many other sites around the world.