American journal of physiology. Renal physiology最新文献

This study tested the hypothesis that ad libitum fluid intake during a 2-h occupational heat stress simulation attenuates increases in renal oxidative stress, inflammation, and acute kidney injury (AKI) risk compared with fluid restriction. Thirteen healthy adults (5 women) completed two 2-h occupational heat stress simulations consisting of eight circuits of treadmill walking and rowing exercise in a wet bulb globe temperature of 33.1 ± 0.2°C. In the drinking trial (Drink), participants were provided 237 mL of a noncaloric sport drink every 15 min and drank ad libitum. In the fluid restriction trial (No Drink), no fluid was provided. Urine and blood samples were analyzed for markers of oxidative stress (thioredoxin-1, TRX-1), inflammation (monocyte chemotactic protein-1, MCP-1), and AKI risk ([IGFBP7·TIMP-2]). During Drink, ad libitum fluid intake was 1,394 ± 316 mL, and reductions in body weight were greater in No Drink (1.3 ± 0.8% vs. 2.8 ± 0.9%, P < 0.001). Peak core temperature was not different between Drink (38.5 ± 0.4°C) and No Drink [38.6 ± 0.4°C, mean difference (upper, lower CI): 0.1 (0.4, -0.1)°C; P = 0.346]. Urine, but not serum TRX-1 (P = 0.254), was elevated at postrecovery and recovery (P < 0.001) but not different between trials (P = 0.743). Serum and urine MCP-1 were elevated at postrecovery and recovery (P < 0.001) but not different between trials (P ≥ 0.407). Urine [IGFBP7·TIMP-2] was elevated at postrecovery and recovery (P < 0.001) but not different between trials (P ≥ 0.096). Ad libitum fluid intake during a 2-h occupational heat stress simulation does not modify biomarkers of systemic and renal oxidative stress and inflammation, nor AKI risk, compared with when fluid is restricted.NEW & NOTEWORTHY Ad libitum fluid intake, consistent with occupational hydration recommendations, does not attenuate renal oxidative stress, inflammation, or acute kidney injury risk during simulated heat stress. These findings challenge the assumption that current hydration recommendations are protective, suggesting that additional strategies are needed to mitigate heat-induced kidney injury in occupational settings.

Prostate inflammation and fibrosis are linked to lower urinary tract symptoms (LUTS) in men. Uropathogenic Escherichia coli (E. coli) infection of the mouse prostate triggers a cascade of immune responses that drive inflammation and fibrosis. A recent study found that lysosome 2-positive (LYZ2+) myeloid cells (fibrocytes) are recruited in a C-C motif chemokine receptor 2 (Ccr2)-dependent manner to the E. coli-infected prostate, where they produce collagen. This study aims to identify factors that drive collagen synthesis in LYZ2+ myeloid cells during E. coli infection. We show that lymphocyte antigen 6 family member (Ly6C)^hi monocytes and their maturation products, Ly6C^hi macrophages, infiltrate the E. coli infected prostate in a Ccr2-dependent manner, that monocytes in the infected prostate produce Tgfb1 RNA, and that E. coli infection activates TGFB signaling and collagen synthesis in LYZ2+ cells. Blockade of macrophage colony-stimulating factor (M-CSF), a factor required for monocyte differentiation into macrophages, reduces macrophage density, TGFB signaling in LYZ2+ cells, and collagen density in the E. coli-infected prostate. These findings highlight a critical role of macrophages in activating collagen synthesis in fibrocytes to drive a fibrotic response to E. coli infection in the mouse prostate.NEW & NOTEWORTHY Prostatic/urethral fibrosis is an emerging cause of urinary voiding dysfunction in aging men and has been linked to prostate inflammation, but cellular mediators and mechanisms of this process are incompletely understood. We provide evidence that Ly6C^hi monocytes and LYZ2+ myeloid cells are recruited to the E. coli infected mouse prostate. Macrophages in the infected prostate synthesize TGFB1 and stimulate collagen synthesis in LYZ2+ cells.

Lupus nephritis (LN) is the renal manifestation of the autoimmune disease systemic lupus erythematosus (SLE). LN is characterized by a dysregulated immune system, the presence of autoantibodies, and renal immune complex deposits, which collectively injure the kidney. However, novel nonimmune pathogenic mechanisms of human LN are continuously uncovered, presenting new challenges as well as opportunities for intervention. Iron accumulation and ferroptosis in the glomerular structure and renal tubules are relatively newly identified pathological features in LN. Ferroptosis is an iron-dependent nonapoptotic form of regulated cell death. Unlike generic oxidative stress mechanisms, ferroptosis occurs when the cellular antioxidative mechanism cannot suppress the oxidation of the cell membrane eventually leading to cell membrane rupture. Since iron absorption and recycling occur in the renal tubules, the renal tissue is particularly susceptible to ferroptosis. Ferroptosis inhibitors that reduce toxic phospholipid hydroperoxides to their corresponding nontoxic alcohols, or trap radicals in phospholipid bilayers, have improved disease outcomes in murine models of SLE/LN. In this review, we discuss mechanisms by which iron accumulation and ferroptosis perpetuate pathology in LN. These studies suggest that ferroptosis is very likely integral to parenchymal cell dysfunction in LN and a novel therapeutic target. The goal of this review is to introduce the fundamentals of iron biology and ferroptosis to clinicians and basic scientists and spur research to identify intracellular proferroptotic enzymes and their protein conjugates as potential targets to improve LN.

Renal outer medullary K⁺ (ROMK) channels are essential for urinary potassium secretion, and their endocytosis prevents excessive K⁺ loss during dietary deficiency. The clathrin adaptor autosomal recessive hypercholesterolemia (ARH) has been implicated in mediating ROMK internalization, yet its physiological significance remains unclear, as hypokalemia is not reported in patients with type 4 familial hypercholesterolemia (FH4) who lack functional ARH. To address this, we investigated potassium homeostasis in ARH knockout (KO) mice, a model of FH4. Despite conserving K⁺ during dietary restriction, ARH-KO mice exhibited exaggerated urinary K⁺ loss when challenged with hydrochlorothiazide, consistent with compensatory upregulation of the thiazide-sensitive sodium-chloride cotransporter (NCC). Immunoblotting revealed significantly higher ROMK and large-conductance Ca²⁺-activated K⁺ channel-α (BKα) protein levels in the renal cortex of ARH-KO compared to wild-type (WT) mice at matched plasma K⁺ concentrations. Because BKα contains NPXY motifs required for ARH binding, we confirmed ARH directly associates with BKα by coimmunoprecipitation. Under potassium-deficient conditions, ARH-KO mice showed impaired downregulation of apical ROMK and BKα, indicating ARH-dependent endocytosis. Interestingly, compensatory mechanisms differed by sex: female KO mice exhibited enhanced NCC abundance and phosphorylation, whereas male KO mice showed reduced epithelial sodium channel (ENaC) cleavage and diminished BK auxiliary subunits relative to WT. These findings 1) establish ARH as a key regulator of ROMK and BKα trafficking in the distal nephron, 2) reveal sex-specific compensatory mechanisms that preserve potassium balance, and 3) underscore the delicate nature of K⁺ homeostasis upon ARH deletion, with maintained normokalemia at the expense of physiological trade-offs involving altered sodium handling.NEW & NOTEWORTHY Renal outer medullary K⁺ (ROMK) and large-conductance Ca²⁺-activated K⁺ channel (BK), both regulated by the clathrin adaptor autosomal recessive hypercholesterolemia (ARH), play essential roles in maintaining potassium balance. Given the life-threatening risks of dyskalemia, it is unsurprising that their activity is controlled by multiple mechanisms, though not without physiological costs. We found that impaired ARH-mediated ROMK and BK internalization triggers activation of alternative potassium-conserving pathways in a sex-specific manner. In females, who are more prone to hypokalemia, this compensation involves thiazide-sensitive sodium-chloride cotransporter (NCC) upregulation, a key player in blood pressure regulation.

Many patients with end-stage kidney disease (ESKD) frequently suffer from both aggressive vascular access stenosis in the venous segment of arteriovenous fistula or arteriovenous graft, and widespread cardiovascular disease (CVD) or peripheral arterial disease (PAD). Despite the magnitude of these clinical problems, the pathogenic role of the uremic state in both of these conditions remains unclear. To investigate the underlying mechanisms, we used porcine-derived arterial smooth muscle cells (ApSMCs) and venous smooth muscle cells (VpSMCs) to examine several key aspects of cell behavior in response to uremic serum. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that 30% of uremic serum was able to stimulate the proliferation of both subtypes of cells equally. Cell migration, measured by the scratch assay, showed that uremic serum increased migration of both cells, but was more robust in VpSMCs. Importantly, uremic serum induced phenotypic switching (e.g., dedifferentiation) in both subtypes of cells, as indicated by increased proliferating cell nuclear antigen expression and reduced calponin expression. Intriguingly, we found that several key aspects of this uremia-induced phenotypic switch were stronger in ApSMCs as compared with VpSMCs, including the production of extracellular matrix (ECM) proteins, such as fibronectin, cellular calcification [high expression of RUNX family transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Krüppel-like factor 4 (KLF-4)], and a proinflammatory state [high expression of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6)]. Our findings suggest that uremia plays an important role in both the aggressive arteriovenous stenosis and CVD/PAD that affect many patients undergoing hemodialysis. This information could contribute to the development of novel uremia-specific therapies for both vascular access dysfunction and CVD/PAD in patients with ESKD.NEW & NOTEWORTHY This study was the first one to directly explore the differential response of arterial VSMCs and venous VSMCs to uremic serum exposure side by side. Both similarities and differences were detected in this in vitro study, which provides insight into the clinical manifestations we observed in patients with ESKD. Furthermore, these results may also be valuable information for uremia-specific therapies for both vascular access dysfunction and CVD/PAD in patients with ESKD.

Hypothyroidism is associated with the desynchronization of central and peripheral circadian clocks; however, its effects on renal rhythmicity remain unclear. This study investigated the impact of short-term hypothyroidism on renal molecular clock oscillations and daily kidney function in male and female rats. Hypothyroidism was induced by thyroidectomy followed by methimazole and CaCl₂ administration for 21 days. Renal handling of solutes and electrolytes and the expression of core clock components were evaluated every 6 h over 24 h. Urinary levels of creatinine, protein, glucose, and sodium and the clearance and fractional excretion (FE) of these solutes exhibited circadian oscillations in control rats. In males, hypothyroidism abolished the rhythmicity of serum creatinine, creatinine clearance (C_Cr), renal glucose clearance (C_glucose), and fractional excretion of glucose, sodium, and potassium; decreased the mesor and amplitude of protein excretion parameters; reduced mesor and amplitude of Bmal1 expression and phase advanced Per2 and Nr1d1 mRNA expression. In females, hypothyroidism reduced the mesor of urinary creatinine, serum glucose, and CCr while delaying its acrophase; increased the mesor of proteinuria and glucosuria and the mesor and amplitude of C_glucose and FE_glucose; and disrupted the circadian pattern of FE_protein and Per2 and Nr1d1 expression in kidney and phase advanced Bmal1 expression. Sodium and potassium daily handlings were more altered in males than in females. No structural damage was found in the kidney of hypothyroid rats. These findings indicate that short-term hypothyroidism desynchronizes the renal circadian clock and disturbs the daily rhythmicity of several renal parameters in a sex-dependent manner, potentially contributing to early-stage kidney dysfunction.NEW & NOTEWORTHY Hypothyroidism alters the kidney circadian clock machinery and renal function in a sex-dependent manner, potentially contributing to early-stage kidney dysfunction. Female rats exhibited more severe rhythmic impairments under hypothyroid conditions, including reduced creatinine clearance, increased protein and glucose loss in urine over 24 h, and disrupted circadian oscillations in renal clock components, indicating a greater susceptibility of females to hypothyroidism-induced metabolic disturbances associated with circadian disruption.

Chronic inflammation contributes significantly to hypertension and associated target organ damage, particularly in the heart and kidneys. Specialized proresolving mediators, a class of bioactive lipids, play key roles in resolving inflammation and maintaining tissue homeostasis. Among them, Maresin 1 (MaR1) has been implicated in cardiovascular regulation and blood pressure control. We hypothesized that MaR1 may mitigate salt-induced hypertension and its related effects in Dahl salt-sensitive (SS) rats. In this study, SS rats were fed a high-salt diet and treated with MaR1. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored. Echocardiography and histology were used to assess cardiac structure, contractility, and fibrosis. Lipidomic profiling quantified inflammation-resolving lipid mediators, and transcriptomic analysis identified organ-specific gene expression changes. MaR1 treatment did not significantly alter MAP, HR, or cardiac structure and function. Echocardiographic and histological evaluations showed no significant changes in cardiac remodeling, contractility, or collagen deposition in the heart or kidney. However, lipidomic profiling revealed shifts in inflammatory lipid mediators, suggesting immunomodulatory and metabolic effects of MaR1. Transcriptomic analysis demonstrated organ-specific gene expression changes, with upregulation of circadian pathways in the heart and modulation of immune signaling in the kidney. Notably, MaR1 influenced circadian blood pressure rhythms, enhancing amplitude and shifting the acrophase, consistent with altered expression of circadian clock genes. Although MaR1 did not affect hypertension development directly, its modulation of lipid metabolism, inflammatory pathways, and circadian regulation suggests therapeutic potential. Future studies should assess longer treatments and combination approaches to clarify its role in cardiorenal disease management.NEW & NOTEWORTHY This study shows that MaR1, a specialized proresolving mediator, influences lipid metabolism and modifies gene expression in the heart and kidney in a salt-sensitive hypertension model, without affecting blood pressure or organ structure. These findings highlight the potential role of MaR1 in regulating inflammation and circadian rhythms associated with cardiovascular and renal diseases.

Proteinuria is both a predictor and mediator of chronic kidney disease (CKD) progression, but treatment options targeting its underlying mechanisms are limited. Emerging evidence suggests that aberrantly filtered serine proteases contribute to the pathogenesis of proteinuria and progressive kidney injury through multiple pathways, including podocyte injury, inappropriate activation of the epithelial sodium channel (ENaC), and tubular complement activation. Serine protease inhibitors, such as aprotinin, camostat mesylate, and nafamostat mesylate, as well as off-target effects of amiloride, have shown promise in preclinical and early clinical studies by mitigating these pathological processes. These drugs reduce proteinuria, sodium retention, oxidative stress, inflammation, and fibrosis. However, clinical translation is hindered by limited data from controlled trials, varying pharmacokinetics, and concerns about systemic adverse effects and long-term safety. Endogenous serine protease inhibitors help maintain proteolytic balance in the kidneys, but their capacity may be overwhelmed in proteinuria. Although complete inhibition could disrupt essential functions, pharmacologic modulation of tubular serine protease activity may be a more effective strategy by preserving beneficial activity while limiting pathological effects. This review synthesizes current knowledge on the pathophysiological role of tubular serine proteases and evaluates the therapeutic potential of their inhibition as a potential target in proteinuric diseases. We identify key knowledge gaps, including the need for mechanistic pharmacodynamic trials, biomarker-guided patient selection using urinary serine protease activity, and long-term efficacy and safety studies. Serine protease inhibitors are a promising, underexplored therapeutic strategy in proteinuric conditions that may complement existing treatments by targeting specific pathogenic mechanisms involved in disease progression.

Kidney disease (KD) has emerged as a major global health crisis and leading cause of morbidity and mortality worldwide, impacting over 850 million individuals. Pathophysiological hallmarks of KD encompass renal tubular cell injury/necrosis, tubulointerstitial fibrosis, vascular dysfunction/rarefaction, and mitochondrial dysfunction, all of which are implicated in disease initiation/progression. Unfortunately, there remains a general lack of effective Food and Drug Administration (FDA)-approved therapeutics for the treatment of KD. Thus, the identification of novel and/or repurposed treatment strategies remains of dire importance. Previously, we identified the 5-hydroxytryptamine 1F receptor (HTR1F) as a modulator of renal mitochondrial homeostasis and demonstrated that mice lacking this receptor exhibit hindered renal recovery following mild ischemia/reperfusion-induced acute kidney injury (I/R-AKI). In addition, we reported that treatment with the HTR1F agonist lasmiditan, an FDA-approved therapeutic for acute migraines, expedites renal recovery following I/R-AKI in mice. Here, we show that lasmiditan treatment following moderate-severe I/R-AKI ameliorates acute tubular injury, mitochondrial dysfunction, tubulointerstitial fibrosis, and vascular rarefaction in the renal cortex of mice, which likely contributes to the enhanced recovery observed. Importantly, we also confirm that this lasmiditan-induced renal recovery is contingent on HTR1F expression. Furthermore, mice lacking the HTR1F exhibit decreased innate renal cortical vasculature, exacerbated rarefaction, and markedly increased mortality rates following moderate-severe I/R-AKI. These findings not only underscore the importance of HTR1F expression and agonism in renal repair and recovery but also further highlight the repurposing potential of lasmiditan for the treatment of AKI and/or KD onset/progression.NEW & NOTEWORTHY In the present study, we confirmed that lasmiditan-induced renal recovery following moderate-severe bilateral ischemia/reperfusion-induced acute kidney injury (I/R-AKI) in mice is dependent on the HTR1F expression. Furthermore, lasmiditan treatment ameliorated acute tubular injury, mitochondrial dysfunction, tubulointerstitial fibrosis, and renal cortical vascular rarefaction postinjury, likely contributing to this enhanced recovery. Interestingly, we also found that mice lacking the HTR1F display decreased innate renal cortical vasculature, exacerbated rarefaction, and exhibit markedly increased mortality following moderate-severe I/R-AKI.