American journal of physiology. Renal physiology最新文献

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.

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.

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.

Black individuals, especially Black females, have higher prevalence of chronic kidney disease (CKD) and greater risk of CKD-related cardiovascular (CV) mortality compared with other racial groups. Patients with CKD have higher CV reactivity compared with those without CKD that contributes to increased CV risk in this patient population. However, race and sex differences in hemodynamic reactivity within CKD have not previously been explored. Given the known race and sex differences in the risk of CKD-related CV disease, we tested the hypothesis that Black individuals, especially Black females, with CKD will have greater CV reactivity to stress. Forty-three Black participants (32 males) and 20 White participants (12 males) with CKD stages III and IV were enrolled. Blood pressure (BP) and heart rate (HR) reactivity were evaluated during three laboratory stressors: mental arithmetic test (MAT), static handgrip exercise (SHG30%), and cold pressor test (CPT). Black participants had greater BP reactivity during MAT and greater HR reactivity during SHG30%, but no difference in CV reactivity during CPT compared with White participants. There were no sex differences in hemodynamic responses across all tests. Black females had greater BP reactivity during MAT and greater HR reactivity during SHG30% compared with White females. Black females had the highest CV responses across all tests. Black individuals, especially Black females, with CKD had greater CV reactivity during stressful stimuli compared with White individuals with CKD. These results highlight demographic influences on CV reactivity that may contribute to differences in CV outcomes in people with CKD.NEW & NOTEWORTHY Among patients with chronic kidney disease, Black individuals-particularly Black females-exhibited heightened cardiovascular responses to different laboratory stressors compared with White individuals. The magnitude and pattern of cardiovascular reactivity varied by race and sex, with differential responses observed depending on the type of stressor applied. Elevated cardiovascular reactivity in Black individuals, especially Black females, may represent a mechanistic link contributing to their disproportionate burden of CKD-related cardiovascular disease.

Acute kidney injury (AKI) induced by ischemia-reperfusion (I/R) contributes to a high rate of morbidity and mortality in many clinical settings. We hypothesized that I/R-induced proximal tubule (PT) injury is associated with inflammation and apoptosis and that PT cell injury may impair Na⁺/H⁺ exchanger isoform 3 (NHE3) activity. This study aimed to investigate the relationship between PT injury and NHE3 activity, analyzing the contribution of the p38MAPK/ezrin signaling pathway. To this end, we used in vivo and in vitro models of I/R. For the in vivo approach, 8-wk-old C57BL/6J mice were subjected to bilateral kidney I/R and compared with the sham-treated group. In vitro, TKPTS cells (mouse proximal tubular cell line) were subjected to I/R by treatment with antimycin A (5 µM) and/or SB203580 (1 µM; p38MAPK inhibitor) or NSC305787 (3.2 µM; ezrin phosphorylation inhibitor) and compared with respective controls. Renal I/R in mice resulted in PT injury, severe inflammation, increased p38MAPK activation, reduced phospho (p-)ezrin immunostaining, and decreased colocalization of NHE3 with both villin and p-ezrin. Similarly, in vitro I/R caused cell apoptosis, increased p38MAPK activation, induced translocation of ezrin from the membrane to the cytosol, and reduced NHE3 activity. Thus, these findings suggest that in ischemic AKI tubulointerstitial injury is driven by inflammation and apoptosis, mediated through p38MAPK activation and altered ezrin function, ultimately impairing NHE3 activity and exacerbating cell injury.NEW & NOTEWORTHY This study demonstrated that renal ischemia-reperfusion (I/R) induces severe damage to the proximal tubular epithelium, mainly by exacerbating inflammatory and apoptotic responses. These responses are mediated by activated p38MAPK, which alters ezrin function and impairs NHE3 activity, exacerbating cell injury.

Acute kidney injury (AKI) is a devastating condition with major complications including death and, in some cases, progression to chronic kidney disease (CKD). We have previously shown that pulsed ultrasound (pUS) can reduce kidney ischemia-reperfusion injury (IRI) by activating the cholinergic anti-inflammatory pathway. The efficacy of a spleen-targeted pUS regimen in AKI of other etiologies and its long-term impact are unclear. Using a new spleen-targeted US approach, pUS was delivered to male mice 24 h before folic acid (FA), lipopolysaccharide, or bilateral kidney IRI. Mice were monitored and assessed for markers of inflammation, renal function, and kidney fibrosis. When compared with sham, mice that received spleen-targeted pUS had reduced plasma TNFα and blood urea nitrogen (BUN) after sepsis-associated AKI, reduced plasma creatinine, and BUN after kidney IRI and reduced plasma creatinine, BUN, and kidney fibrosis after FA administration. pUS-treated mice displayed reduced myeloid cell infiltration to the kidneys after FA and IRI. In sham-treated mice, markers associated with ongoing maladaptive repair including Sox9, Wnt2, and Wnt4 were increased on day 14 after FA in comparison with pUS-treated mice. These data demonstrate that pulsed ultrasound of the spleen is a novel, safe, and effective therapy for the prevention of AKI of multiple etiologies and the subsequent development of CKD. Findings from this study are critical for advancing human translation of ultrasound as a preventative measure for AKI and CKD.NEW & NOTEWORTHY We developed a safe and effective pulsed ultrasound (pUS) protocol targeting the mouse spleen to block inflammation and reduce AKI of multiple etiologies. By using a model of the AKI to CKD transition, we demonstrated the long-term benefits of pUS. The findings of these studies will be used to advance the human translation of spleen-targeted US as a preventative measure for AKI and CKD.

Chronic kidney disease (CKD), characterized by persistent inflammation and progressive renal fibrosis, remains a major therapeutic challenge due to an incomplete understanding of its pathogenesis. Since C1q/TNF-related protein 1 (CTRP1) plays a potential role in fibrosis and inflammation in other tissues, we investigated the role of CTRP1 in patients and mice with CKD. Here CTRP1 expression was increased in plasma and decreased in the kidneys of patients with CKD. Upregulation of renal CTRP1 with adeno-associated-CTRP1 was associated with decreased renal fibrosis, inflammation, macrophage accumulation, and activation in mice models. Mechanistically, CTRP1 abolished the expression of transforming growth factor beta 1 (TGFβ1)-induced macrophage M2-associated genes and the transcriptional regulators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). In addition, upregulation of CTRP1 could partly downregulate lipopolysaccharide (LPS)-stimulated expression of proinflammatory genes in vitro. Conditioned media from TGFβ1-CTRP1-pretreated macrophages could less efficiently stimulate fibroblast activation compared with those from TGFβ1-pretreated macrophages. Thus, our study reveals local CTRP1 as a potential regulator of chronic inflammation and kidney fibrosis through regulating macrophage activation. Taken together, these findings support renal CTRP1 as a novel therapeutic target for CKD.NEW & NOTEWORTHY Augmenting renal CTRP1 expression mitigates chronic inflammation and fibrosis by inhibiting pathological macrophage activation. These findings offer a novel mechanism of kidney inflammation and fibrosis. CTRP1 can be considered as a predictive marker and/or therapeutic target for patients with CKD.