American journal of physiology. Renal physiology最新文献

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.

Vasopressin plays a major role in the pathogenesis of autosomal dominant polycystic kidney disease (PKD), the fourth leading cause of end-stage kidney disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is the only approved treatment. The role of vasopressin V1a and V1b receptors (V1aR and V1bR) has not been studied. Pkd1^RC/RC mice were allocated to control and 5 experimental groups treated with tolvaptan, OPC21268 (V1aR antagonist), SSR149415 (V1bR antagonist), tolvaptan plus OPC21268, or tolvaptan plus SSR149415, from 4 to 16 wk of age, to compare their separate effects on PKD and to determine whether addition of OPC21268 or SSR149415 potentiates or hinders the therapeutic effect of tolvaptan. Tolvaptan significantly reduced total kidney volume (TKV) measured by MRI and rate of TKV growth. OPC21268 had no effect on PKD when administered alone. SSR149415 reduced TKV and TKV growth in female mice only. The sex-dependent effect may be due to the increased expression of the V2 and V1b receptors in the kidneys of female compared with male Pkd1^RC/RC mice. When OPC21268 or SSR149415 was administered in combination with tolvaptan, TKV, TKV growth, kidney weights, kidney weights adjusted by body weight, cyst indices and volumes, and plasma urea concentrations were not different from those observed with administration of tolvaptan alone. These results indicate that the beneficial effects of tolvaptan in PKD are mainly mediated by the inhibition of V2 receptors and provide no support for clinical trials of V2R antagonists combined with either V1a or V1b receptor antagonists.NEW & NOTEWORTHY Currently, the vasopressin V2 receptor antagonist tolvaptan is the only approved treatment for autosomal dominant polycystic kidney disease (ADPKD). It has been suggested that vasopressin acting on V1a or V1b receptors may also affect its development. We show that a V1aR antagonist has no effect in an ADPKD mouse model (Pkd1RC/RC), whereas a V2R antagonist has a modest attenuating effect in female mice only. Neither potentiates or hinders the beneficial effect of tolvaptan when administered in combination with this drug.

The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin system (RAS) due to increased renin release from juxtaglomerular cells. However, no previous study has functionally assessed the potential involvement of the intrarenal RAS in this model. Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), where it plays a key role in regulating the intrarenal RAS under physiopathological conditions. In the present study, we used a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice underwent either a sham operation or clipping the left renal artery using a polyurethane cuff with an internal diameter of ∼2.7 mm for 1 mo. Subsequent analyses included blood pressure measurement, renal injury assessment, examination of epithelial Na⁺ channel (ENaC) subunit expression, and evaluation of plasma and intrarenal renin and angiotensin II levels. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin levels. Moreover, renal medullary α-ENaC mRNA and protein expression were elevated by clipping in floxed mice, which was blunted in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy.NEW & NOTEWORTHY Nonspecifically targeting the RAS in renovascular hypertension and ischemic nephropathy is only partially effective and also limited by class toxicities of hyperkalemia and acute decline of renal function. Our results help understand the CD PRR-mediated local mechanism in the pathogenesis of renovascular hypertension and ischemic nephropathy, and also support CD PRR as a potential therapeutic target for selective inhibition of the intrarenal RAS to treat this devastating disease.

Antigen-presenting cells (APCs) are present in the renal interstitium and may modulate tubular function. We hypothesize that angiotensin II (Ang II) induces a prohypertensive phenotype in renal APCs, contributing to decreased natriuresis and hypertension. We evaluated the role of renal APCs as modulators of blood pressure (BP) in CD11c.DOG mice injected with diphtheria toxin (DT). Elimination of 70% of renal APCs by DT prevented the increase in BP, cardiac hypertrophy, decreased natriuresis, and sodium-potassium-chloride cotransporter type II (NKCC2) activation. Second, we compared the effect of the adoptive transfer of renal and splenic APCs on BP and natriuresis in wild-type mice. Renal APCs from Ang II mice induced a transient BP increase and reduced natriuresis. In contrast, renal APCs from control mice or splenic APCs from control or Ang II-infused mice did not modify BP or natriuresis. In CD11c.DOG mice depleted of dendritic cells (DCs), the adoptive transfer of renal APCs from Ang II-infused mice increased the BP. However, RAG1 knockout mice, devoid of T cells, did not present an increase in BP after the adoptive transfer of renal APCs of Ang II-infused mice. Renal APCs from Ang II-infused mice showed increased NOX2, SGK1, and pro-inflammatory cytokine expression compared with control renal APCs. Cell-tracking experiments of transferred renal APCs into a normotensive host showed preferential homing to the host kidneys and higher receptor expression for the renal-homing chemokine, fractalkine (CX3CR1). We conclude that renal APCs acquire a prohypertensive phenotype due to high Ang II levels, conferring the ability to modulate renal sodium handling.NEW & NOTEWORTHY Ablation of APCs prevented Ang II-induced hypertension, NKCC2 activation, and preserved natriuresis. Transfer of renal APCs from Ang II-mice increased BP and reduced natriuresis in recipient mice; renal APCs from normotensive mice or splenic APCs from Ang II-infused mice had no effect. The effect of renal APCs was dependent on the presence of T cells. Renal APCs from Ang II-mice showed preferential destination to the kidney and increased expression of cytokines.

Adhesion G protein-coupled receptors (AGPCRs) are a class of seven-transmembrane receptors that sense cell-to-cell and cell-to-extracellular matrix transient adhesive events. AGPCRs are physiologically relevant and regulate processes throughout the body. However, the physiological roles of many AGPCRs are undefined. Unlike G protein-coupled receptors (GPCRs) that bind soluble agonists, AGPCRs uniquely depend on extracellular interactions and stimuli to facilitate endogenous activation by a tethered peptide agonist. Therefore, it is paramount to determine the cellular localization of AGPCRs to begin unraveling their functional roles. In the present work, we have identified the most abundant AGPCRs expressed in the murine kidney and determined their cellular localization through a combination of single-nucleus RNA sequencing and RNAscope fluorescent in situ hybridization. We not only report the transcriptional abundance of six AGPCRs that are expressed in a cell-specific manner but also demonstrate that Adgrf1, a receptor with low but specific abundance by snRNAseq, is detected in a subset of principal cells by RNAscope. In addition, we identify cell-specific transcript variants of Adgrf5 in the kidney, supporting a significant role of alternative splicing in AGPCR physiology. These data will assist in the generation of tissue- and cell-specific hypotheses and enable future investigations into the physiological roles of AGPCRs in the kidney and other tissues.NEW & NOTEWORTHY Adhesion G protein-coupled receptors (GPCRs) are a unique class of receptors that regulate numerous physiological processes throughout the body. Here, we identify and localize the AGPCRs expressed in the mouse kidney using a multimodal approach. This work will provide a foundation for future investigations into the novel physiological roles of AGPCRs in the kidney.