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In the dense circulatory system of the kidney, as in all vascularized tissues, pericytes enwrap capillaries and microvessels to regulate angiogenesis, stabilize microvascular networks and control blood flow by vasoconstriction. Specialized renal pericytes known as mesangial cells provide physical support to glomerular capillaries, whereas a subset of juxtaglomerular arteriolar pericytes control the local blood pressure in the glomerulus via contraction and influence systemic blood pressure by secreting renin. Similar to pericytes from many other organs, cultured human renal pericytes give rise to mesenchymal stem/stromal cells, suggesting a role of perivascular cells in renal homeostasis and regeneration. On the other hand, pericytes directly contribute to renal fibrosis, and mesangial cells may have an essential role in the development of glomerulosclerosis and other nephropathies. From their early emergence in the renal embryonic rudiment to their distribution in diverse perivascular niches in the adult organ, we review the anatomy and function of pericytes in the healthy and diseased kidney. Many aspects of the ontogeny, specification and functional specialization of renal pericytes remain elusive. The development of powerful models in the easily accessible and genetically tractable zebrafish will help to uncover the multiple facets of these cells.

Key Points Dendritic cells (DCs) and macrophages are distinct cell types, but demonstrate similarities in terms of ontogeny, phenotype, and function Both of these cell types are present within the renal interstitium and are critical to homeostatic regulation of the kidney environment The numbers of DCs and macrophages in the kidney increase following renal injury A variety of DC and macrophage subtypes exist, each with distinct phenotypes and activities, and many can be identified based on panels of cellular markers The manifestation of glomerular or tubular kidney disease, as well as disease outcome in preclinical models, is determined by the subtype of DC and/or macrophage involved A number of pharmacological or genetic approaches are available to deplete or eliminate DCs or macrophages in preclinical models, but the effects of such interventions are not renal-specific Renal dendritic cells and macrophages are key factors in the initiation and propagation of renal disease and tissue regeneration. In this Review, the authors discuss the common and distinct characteristics of dendritic cells and macrophages as well as current understanding of the renal-specific functions of these important phagocytic, antigen-presenting cell types in potentiating or mitigating intrinsic kidney disease. Renal dendritic cells (DCs) and macrophages represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune-intelligence activity; they induce and regulate inflammatory responses to freely filtered antigenic material and protect the kidney from infection. Tissue-resident or infiltrating DCs and macrophages are key factors in the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration, regardless of the aetiological and pathogenetic mechanisms. The identification, and functional and phenotypic distinction of these cell types is complex and incompletely understood, and the same is true of their interplay and relationships with effector and regulatory cells of the adaptive immune system. In this Review, we discuss the common and distinct characteristics of DCs and macrophages, as well as key advances that have identified the renal-specific functions of these important phagocytic, antigen-presenting cells, and their roles in potentiating or mitigating intrinsic kidney disease. We also identify remaining issues that are of priority for further investigation, and highlight the prospects for translational and therapeutic application of the knowledge acquired.

Cellular senescence refers to a cellular phenotype characterized by an altered transcriptome, pro-inflammatory secretome, and generally irreversible growth arrest. Acutely senescent cells are widely recognized as performing key physiological functions in vivo promoting normal organogenesis, successful wound repair, and cancer defense. In contrast, the accumulation of chronically senescent cells in response to aging, cell stress, genotoxic damage, and other injurious stimuli is increasingly recognized as an important contributor to organ dysfunction, tissue fibrosis, and the more generalized aging phenotype. In this review, we summarize our current knowledge of the role of senescent cells in promoting progressive fibrosis and dysfunction with a particular focus on the kidney and reference to other organ systems. Specific differences between healthy and senescent cells are reviewed along with a summary of several experimental pharmacological approaches to deplete or manipulate senescent cells to preserve organ integrity and function with aging and after injury. Finally, key questions for future research and clinical translation are discussed.

Maladaptive proximal tubular (PT) epithelial cells have been implicated in progression of chronic kidney disease (CKD), however the complexity of epithelial cell states within the fibrotic niche remains incompletely understood. Hence, we integrated snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease. We demonstrate that in injured kidneys, a subset of HAVCR1 + VCAM1 + PT cells acquired an inflammatory phenotype, upregulating genes encoding chemokines, pro-fibrotic and senescence-associated proteins and adhesion molecules including ICAM1 . Spatial transcriptomic and multiplex-immunofluorescence determined that specifically these VCAM1 + ICAM1 + inflammatory PT cells localised to the fibrotic niche. Ligand-receptor analysis highlighted paracrine signaling from inflammatory PT cells mediating leucocyte recruitment and myofibroblast activation. Loss of HNF4α and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting inflammatory tubular cells by administering an AP-1 inhibitor or senolytic agent ameliorated inflammation and fibrosis in murine models of kidney injury, hence these cells may be a tractable target in CKD. The complexity of epithelial cell states in the fibrotic niche in the context of chronic kidney disease remains incompletely understood. Here the authors integrate snRNA and ATAC-seq with high-plex single-cell molecular imaging to generate a spatially-revolved multiomic atlas of human kidney disease.

Background: Quality assurance of linear accelerators (linacs) is an important part of ensuring accurate radiotherapy treatment deliveries. The aim of this study is to investigate the role of gravity on the positional accuracy of multileaf collimator (MLC) leaves during complex radiotherapy treatments on linacs. This investigation is based on the analysis of the machine log files from five different linacs in multiple centers. Materials and Methods: Three main categories of deliveries were considered: Picket fence, volumetric modulated arc therapy (VMAT) (both delivering with continuous gantry rotation), and sliding gap tests delivered at cardinal gantry angles, to determine the error of the MLC in relation to the gantry angle. Results: Analysis of picket fence tests revealed a dependence of the error upon the gantry angle. For the majority of deliveries, the MLC showed greater error at gantry angles 270 and 90. The errors computed for the cardinal angles for sliding gap tests were all statistically different with greatest error arising at gantry angle 270 and least error at gantry 90. For picket fence, sliding gap, and VMAT cases, MLC errors were dependent on the gantry angle. Conclusions: The errors in leaf positioning were found to be dependent on the gantry angle. For sliding gap tests, the error was greater at gantry angle 270° and 90° and less when the leaf motion was perpendicular to the force of gravity.

MicroRNAs may act as diagnostic and prognostic biomarkers of chronic kidney disease and are functionally important in disease pathogenesis. To identify novel microRNA biomarkers, we performed small RNA-sequencing on plasma from individuals with type 2 diabetes, with and without chronic kidney disease. MiR-190a-5p abundance was significantly lower in the circulation of type 2 diabetic patients with reduced function compared to those with normal kidney function. In an independent cohort of patients with chronic kidney disease of diverse aetiology, miR-190a-5p abundance predicted disease progression in individuals with no or moderate albuminuria ( < 300 mg/mmol). miR-190a-5p expression in kidney biopsy tissue correlated with the level of miR-190a-5p in the circulation and with estimated glomerular filtration rate, tubular mass and negatively with histological fibrosis. Administration of a miR-190a-5p mimic in a murine ischaemia-reperfusion injury model in male mice reduced tubular injury and fibrosis and increased expression of genes associated with tubular health. Our analyses suggest that miR-190a-5p is a biomarker of tubular cell health, low circulating levels may predict chronic kidney disease progression independent of existing risk factors and strategies to preserve miR-190a-5p may be an effective treatment for restoring tubular cell health following kidney injury. Chronic Kidney Disease affects 1 in 10 people worldwide with prevalence continuing to rise, thus there is a need to identify novel biomarkers that can add value to existing clinical and biochemical risk predictors. Here the authors identify miR190a-5p as potential indicator of kidney health and disease progression in patients with chronic kidney disease.

Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity ( Kmo null mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmo null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type ( Kmo wt ) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness. Kidney disease: drug target for acute injury following reperfusion Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of kynurenine 3-monooxygenase ( KMO ), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO -mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.

When COVID-19 shuttered schools across the nation, it propelled higher education institutions into uncharted territories. Institutions had to make rapid decisions in a short period of time with limited information or direction. In these uncertain and challenging times, pharmacy academics in the United States and around the world reached out to one another to discuss, share, and learn. What began with a few members of the Student Services Personnel Special Interest Group (SIG) grew to many members who banded together as a team through open discussions to innovative problem-solving. Working together through open discussions created a setting that promoted diverse ideas, multiple perspectives, and a depth of knowledge to address some of the most challenging issues faced by pharmacy education. When partnering together, institutions had a much greater resource of knowledge and support that could be leveraged to broadly benefit the Academy.

Several Doctor of Pharmacy programs have rescinded their requirement for applicants to complete the Pharmacy College Admissions Test, modified their requirements for prerequisite coursework, and reduced the minimum grade point average required for admission. As schools and colleges of pharmacy begin to use these and other more holistic approaches to recruitment and admission, the quantity and quality of students in the applicant pool will continue to shift. In alignment with their unique mission, values, and vision statements, pharmacy programs have also expanded aspects of their application and review process to increasingly focus on applicants’ leadership skills, community service, teamwork, collaboration skills, and paid and volunteer work. These aspects allow them to look beyond a candidate’s academic performance and instead emphasize skills and affective domain areas that are aligned with the Accreditation Council for Pharmacy Education standards and Center for the Advancement of Pharmacy Education outcomes. Ways in which pharmacy schools and colleges can refine their recruitment and admissions processes to better align with their unique curricular and programmatic niche areas are discussed.

Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow–derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10–mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10–mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.