American journal of physiology. Renal physiology最新文献

Ischemia-reperfusion injury (IRI) remains a critical challenge to the survival of kidney transplantation (KTX) graft, with no effective prevention or treatment strategies currently available. Neuronal nitric oxide synthase 1β (NOS1β), the predominant splice variant of NOS1 and the main source of NO in the macula densa (MD), mediates tubuloglomerular feedback and regulates glomerular filtration rates. NOS1β activity in the MD is influenced by renal pH; however, the role of pH-dependent regulation of NOS1β in mitigating IRI and protecting transplanted kidney graft function remains unclear. To explore this, C57BL/6J mice were given oral sodium bicarbonate (NaHCO₃) or NaCl for 2 wk before KTX. Blood and urine pH, NOS1β expression, NO levels, and transplant outcomes were evaluated. MD-specific NOS1 knockout (MD-NOS1KO) mice were used to assess the direct role of NOS1β. NOS1β expression decreased by approximately 60% 3 days after KTX. MD-NOS1β deletion exacerbated graft injury. NOS1β activities showed a strong tubular pH dependence, with maximal activity near pH 8.0. Bicarbonate treatment increased NOS1β expression in the MD by 65% and significantly improved graft outcomes, lowering plasma creatinine by ∼30% relative to NaCl-treated group. These protective effects were absent in MD-NOS1KO mice. Proteomic analysis revealed 718 differentially expressed proteins, with several showing enrichment in NO signaling, tissue repair, and inflammatory response pathways. In summary, MD-NOS1β downregulation after transplantation contributes to graft injury. Raising renal pH with bicarbonate enhances NOS1β activity and protects graft function, suggesting a potential therapeutic strategy to reduce IRI in kidney transplants.NEW & NOTEWORTHY This study reveals that raising renal tubular pH with oral bicarbonate enhances macula densa-specific NOS1β activity, protecting against ischemia-reperfusion injury in kidney transplants. These benefits are lost in macula densa NOS1β knockout mice, confirming its key role in graft protection. The findings suggest that modulating renal pH is a promising, noninvasive strategy to improve transplant outcomes by targeting macula densa-NOS1β.

Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show that exercise slows age-related decline in kidney function and protects against acute kidney injury (AKI). We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress. We evaluated running-induced adaptations in 10-14-wk-old C57BL/6J male and female mice subjected to voluntary running or in male mice subjected to forced treadmill running. We evaluated renal perfusion with contrast-enhanced ultrasound and assessed kidney function by measuring the ability to clear a volume load. In addition, we performed flow cytometry, cytokine array, histopathology, and bulk mRNA sequencing. We found that exercise significantly increased cortical microvascular blood volume (P = 0.0085), as indicated by increased plateau contrast signal intensity. In addition, exercised male, but not female, mice excreted significantly more urine in the first hour after a saline bolus (P = 0.0055). At the cellular level, we observed a significant increase in kidney resident macrophages (KRMs; CD45⁺CD11b⁺F4/80^hi) after treadmill training in male mice. Finally, bulk mRNA sequencing suggested that treadmill training induced changes relating to water and sodium handling as well as angiogenesis and wound healing. These data suggest that exercise alters the immune landscape of the kidney, increases renal microvascular volume, and improves sensitivity of the pressure diuresis response. Future studies will test the hypothesis that macrophages cause the functional adaptations observed.NEW & NOTEWORTHY The kidneys exhibit functional and cellular adaptations to exercise, such as increased renal cortex microvascular volume, as indicated by increased signal intensity of contrast-enhanced ultrasound. Exercise improves efficiency of pressure diuresis in male mice, reducing time needed to excrete an isotonic volume excess. At the cellular level, exercise expands kidney resident macrophage populations and alters transcriptional pathways relating to water and sodium handling, angiogenesis, and wound healing.

The vascular supply of the urinary bladder is embedded within a highly dynamic environment that includes alternating cycles of regional compression or stretching during bladder filling, sustained continence, and voiding. These place unique demands on the vasculature to maintain tissue perfusion, fluid homeostasis, and immune surveillance. Understanding this vascular regulation is also highly relevant to defining mechanisms of organ reperfusion following pelvic surgery, pelvic venous insufficiency, and the impacts of diabetes and ischemia on urinary function. There is limited anatomical knowledge on the organization of this vascular network, so we aimed to determine if there are stereotypical features associated with the mouse urinary bladder. We applied advanced microscopy and anatomical visualization methods to samples of the entire bladder viewed as a whole mount, including intravital tomato lectin labeling of the arterial vasculature, multichannel immunofluorescence, tissue clearing, light sheet, and confocal microscopy. We developed a comprehensive multiscale three-dimensional anatomical map of the stereotypical arterial and venous networks associated with the mouse urinary bladder in both sexes, showing that the primary features of this network are established by the early postnatal period, before maturation of voiding and continence reflexes. These outcomes provide the foundation for probing mechanisms that underpin physiological and pathophysiological changes in the urinary bladder vascular network and a resource to guide more refined experimental perturbation, analysis, and interpretation of vascular function/dysfunction in mouse models. This new knowledge on the structure of the urinary bladder vascular network will also benefit tissue engineering efforts seeking to restore or replace this organ.NEW & NOTEWORTHY The vasculature of the urinary bladder is embedded within a highly dynamic environment impacted by cycles of voiding and continence, placing unique demands on tissue perfusion and immune surveillance. This study has applied multiscale microscopy to reveal stereotypical vascular patterning in specific regions and tissues of the urinary bladder of male and female mice, providing a new understanding of organ circulatory support and a resource for studies on bladder function, pathophysiology, and organ engineering.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder leading to kidney cyst formation and loss of kidney function. The major causative genes Pkd1 and Pkd2 encode for the ciliary proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are involved in ciliary functions. Within PKD1-defective cells, the accumulation of misfolded PC1 proteins triggers the unfolded protein response (UPR). Among the pathways activated, the ER-associated degradation (ERAD), mediated by proteins such as valosin-containing protein (VCP), aims to alleviate the unfolded or misfolded protein burden. Our study investigates the genetic relationship between VCP and PC1-dependent cystogenesis. We found that the pharmacological inhibition of VCP ameliorates the cystic phenotype in Pkd1-knockout mice. This effect is associated with increased ER stress-dependent apoptosis in PC1-deficient cells. In addition, we discovered that VCP is localized in the primary cilia and its inhibition affects cilia assembly and reduces the cilia length.NEW & NOTEWORTHY Our findings identify VCP as a novel ciliary protein and a potential therapeutic target for ADPKD. We confirmed that VCP inhibition reduces cyst burden in vivo and selectively induces apoptosis in PC1-deficient cells in vitro via UPR-activation. In addition, VCP regulates cilia assembly and morphology, binding together proteostasis and ciliary dynamics. The results of this study support VCP as a modulator of cystogenesis and offer a novel therapeutical strategy for ADPKD. By selectively promoting apoptosis in PC1-deficient cells and modulating their ciliary functions, VCP inhibition may offer a novel approach to treat ADPKD.

Human pluripotent stem cell-derived kidney organoids have demonstrated utility in modeling kidney development and genetic disease. Autosomal recessive polycystic kidney disease (ARPKD) is an inherited developmental cystic kidney disease of high morbidity and mortality that lacks directed therapy. To overcome the limitations of animal models and stimulate drug discovery, ARPKD organoids have previously been subject to well-described cystogenic mechanisms for use in therapeutic screens. Although these studies have validated genotype-phenotype correlations and cystogenic response of ARPKD organoids as similar to existing in vitro models, novel cystogenic mechanisms that expand potential therapeutic targets have yet to be uncovered. Here we use a combination of human induced pluripotent stem cell-derived ARPKD and isogenic wild-type organoids, native kidney and organoid single-cell RNA sequencing, decedent human ARPKD tissue, and targeted mechanistic studies to describe PTH1R as a stimulatory G-protein-coupled receptor, which instigates a cystogenic signaling cascade in developmental cystic kidney disease. Our findings demonstrate the utility of kidney organoids as an in vitro model for pathomechanisms of rare diseases, which lack faithful animal models.NEW & NOTEWORTHY Stem cell-derived kidney organoids enable human genetic disease modeling to identify the parathyroid hormone 1 receptor as a potential new therapeutic target for developmental polycystic kidney disease.

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in purine metabolism that may influence cellular responses to injury. We evaluated the effects of prophylactic MTAP inhibition in mouse models of ischemia-reperfusion and cisplatin-induced acute kidney injury (AKI). MTAP inhibition was confirmed by the accumulation of methylthioadenosine. Treated mice showed reduced renal injury and decreased tubular damage. Transcriptomic analysis revealed protection from inflammatory and stress pathways while maintaining oxidative phosphorylation, fatty acid metabolism, and epithelial integrity-related genes. Analysis of human single-cell RNA sequencing data from the Kidney Precision Medicine Project indicated that MTAP is highly expressed in kidney injury marker-positive adaptive proximal tubule cells, which display both reparative and maladaptive features during AKI. These findings highlight MTAP as a potential therapeutic target for modulating injury responses in AKI.NEW & NOTEWORTHY We show that prophylactic MTAP inhibition protects against experimental AKI in mice. Transcriptomic data indicate that MTAP inhibition suppresses epithelial stress and maladaptive repair-related gene programs. Single-cell analysis of human AKI biopsies supports a role for MTAP in injured proximal tubule subpopulations, identifying it as a potential therapeutic target in AKI.

Trauma and shock often severely affect the kidneys. This can lead to trauma-related acute kidney injury (TRAKI), which significantly increases the risk of adverse outcomes. To study the pathophysiology of TRAKI, we established a murine model of combined blunt thoracic trauma and pressure-controlled hemorrhage [trauma and hemorrhagic shock (THS)] that induces mild transient TRAKI. The mice displayed early and transiently increased plasma creatinine, urea, and neutrophil gelatinase-associated lipocalin and urine albumin, resolving 5 days after TRAKI induction. Morphological changes were only observed at the microscopic level, where proximal tubular cell damage and brush border loss were evident. We furthermore found kidney stress responses, for example, with induced heme oxygenase-1 expression in tubules. The upregulation of inflammatory mediators and kidney injury markers was followed by elevated leukocyte numbers, mainly consisting of monocytes/macrophages. Proteomic analyses revealed a distinct time course of intrarenal processes following trauma. Three-dimensional x-ray-based whole organ histology by contrast-enhanced microcomputed tomography showed significant impairment of capillary blood filling, particularly during the first day after THS, which was partly resolved by day 5. Our novel murine TRAKI model revealed previously unknown aspects of the complex temporal pathophysiologic response of the kidney along the nephron following trauma and hemorrhage, which may provide mechanistic starting points for future therapeutic approaches.NEW & NOTEWORTHY This study introduces a murine model of trauma-related acute kidney injury (TRAKI) via combined blunt thoracic trauma and hemorrhage, revealing transient kidney dysfunction despite normal morphology. Early damage to proximal tubular cells, inflammatory responses, and induction of stress markers like heme oxygenase-1 were observed. Proteomic analyses uncovered distinct intrarenal changes, whereas three-dimensional microcomputed tomography showed capillary blood supply impairment, resolving by day 5. These findings shed light on TRAKI's pathophysiology and may inform future therapeutic strategies.

The formation of new blood vessels is crucial for tumor and metastatic progression. Consequently, targeted therapies directed toward the vascular endothelial growth factor (VEGF) pathway have significantly improved treatment outcomes in several malignancies. These treatment modalities are frequently used in current oncologic practice, as monotherapy or in combination with other anticancer regimens such as immune checkpoint inhibitors (ICIs), to enhance the anticancer effects. Despite their proven efficacy, anti-VEGF therapies are also known to cause substantial kidney toxicity. Common kidney side effects include hypertension, proteinuria, kidney dysfunction, thrombotic microangiopathy, and in some cases, kidney failure. These adverse effects pose significant challenges in clinical practice, as kidney damage can lead to lower dosing of anticancer treatment and compromise quality of life. The mechanisms underlying kidney toxicity associated with anti-VEGF therapies, including in combination with ICIs, are poorly understood. A deeper understanding of these mechanisms is essential for mitigating kidney damage and preserving kidney function during treatment. This review aims to explore the role of VEGF in kidney physiology, the incidence of kidney toxicities associated with anti-VEGF therapies, and the potential mechanisms driving these toxicities, with particular emphasis on the endothelin, nitric oxide, and prostanoid pathways. In addition, the review will address the kidney effects observed when anti-VEGF therapies are combined with ICIs, as both treatment modalities are independently associated with kidney-related adverse effects, along with the underlying mechanisms involved.