American journal of physiology. Renal physiology最新文献

Renal oxygenation is essential for maintaining kidney function. Disruptions in oxygen delivery can lead to renal hypoxia, which can exacerbate kidney injury through multiple pathways, including inflammation, oxidative stress, and ischemia-reperfusion injury. Despite the recognized importance of oxygenation in renal pathology, noninvasive and reliable methods for assessing kidney oxygen levels are limited. Current techniques either lack sensitivity or involve invasive procedures, restricting their use in routine monitoring. Therefore, there is a pressing need for innovative approaches to map renal oxygenation, particularly in kidney injury. This study evaluated electron paramagnetic resonance (EPR)-based oxygen imaging using the paramagnetic tracer Ox071 to map kidney oxygen levels in mice with cyclophosphamide-induced kidney injury. Urine partial pressure of oxygen (Po₂) was also assessed as a potential surrogate marker. EPR oximetry accurately measured kidney oxygen distribution, revealing a temporary increase in Po₂ post-injury. Urine oximetry, however, did not reliably reflect changes in kidney oxygenation. Furthermore, EPR oximetry provided high-resolution spatial mapping of oxygen levels within the kidney, allowing for a detailed understanding of the impact of hypoxia on renal tissue. EPR oximetry is a promising, noninvasive tool for monitoring renal oxygenation, offering high-resolution mapping and longitudinal assessment. Its ability to provide detailed information about oxygen distribution within the kidney makes it a valuable tool for studying the pathophysiology of renal diseases and for developing novel therapeutic strategies.NEW & NOTEWORTHY Quantitative spatially resolved measurement of renal oxygenation has the potential to guide clinical decision making in renal disorders such as acute kidney injury. In this study, we demonstrate the utility of electron paramagnetic resonance imaging to provide noninvasive and quantitative high-resolution mapping of kidney oxygen concentrations.

Transport across cells of the renal tubule differs between females and males, possibly as a consequence of varying abundance of transport proteins along the nephron. We hypothesized that sex-specific differences in the physiological responses and in transport protein abundances exist in the context of acid-base challenges. We used female and male C57Bl/6J mice and challenged them with acid (NH₄Cl) or base (NaHCO₃) in their drinking water for 8 days. Blood and urine samples were collected at baseline and at the end of the experimental period before kidneys were harvested and protein abundances determined. In response to NH₄Cl challenge, the significant decreases in urine pH, blood HCO₃^-, and base excess were similar in both sexes despite a smaller intake of NH₄Cl in male compared with female mice. In response to NaHCO₃ challenge, urine pH significantly increased in both sexes; however, blood pH, HCO₃^-, and base excess were increased significantly and to a greater extent in male compared with female mice. Two-way analysis of variance demonstrated that out of the 12 tested proteins, 7 were significantly affected by sex, 7 were significantly affected by treatment, and the interaction of sex and treatment was significant for Na⁺/K⁺/2Cl^- cotransporter, NKCC2. In summary, our study demonstrates 1) sex differences in protein abundance, 2) proteins are affected differentially in response to acid-base challenges, and 3) NKCC2 is a new and potentially important player in acid-base regulation.NEW & NOTEWORTHY Disturbances in acid-base regulation are common and can have detrimental effects. Here, we provide evidence that acid-base disturbances in males and females are consistent with female mice being able to defend acid and base challenges more effectively. Our data have potential clinical importance in humans regarding the treatment of acidosis and alkalosis in males versus females.

Parietal epithelial cells (PECs) have been implicated in the pathogenesis of glomerulosclerosis in rodent models, and novel technologies are beginning to unravel their contributions to human glomerular disease. Here, we report the development, validation, and application of a deep learning approach to analyze the PEC population in over 14,000 glomeruli from nephrectomy samples from patients with minimal overt chronic kidney disease (CKD). This analysis revealed a striking correlation between PEC density and podocyte density. Reduced PEC density was also associated with aging and the presence of diabetes. Furthermore, the PEC density in normal-appearing glomeruli was associated with the frequency of glomerular pathology, including global and segmental glomerulosclerosis, in the same patient sample. Patients with low PEC density had gene expression changes consistent with cellular stress in PECs. These observations support a link between PEC population and the progression of CKD.NEW & NOTEWORTHY Little is known about the contribution of PECs to human chronic glomerular disease. We developed, validated, and deployed deep learning image analysis tools to analyze the relationship between PECs and clinical and histopathologic risks of glomerular disease progression in human nephrectomy samples. These analyses revealed a novel link between PEC depletion and early evidence of chronic glomerular disease. The tools developed can be applied to many applications in the study of human kidney disease.

Renal dysfunction leads to critical health conditions, including acute kidney injury (AKI) and chronic kidney disease (CKD), and is a driver of hypertension. Despite their global prevalence and impact, the pathophysiology for all kidney disease subtypes is incompletely understood; therefore, many patients progress to kidney failure, needing dialysis and transplantation. This review highlights the role of pannexins-a family of channel-forming glycoproteins-in renal physiology and pathophysiology. Compared with other organ systems such as the brain and cardiovascular system, relatively little is known about the function of pannexins in the kidney. However, recent findings indicate that pannexins may be potential therapeutic targets in the treatment of hypertension, AKI, and CKD, though further research is needed to fully understand their precise role in renal health and disease.

In the current study, we used SS^p67phox-/- to assess the involvement of oxidative stress in the regulation of renal blood flow during the development of salt-sensitive hypertension in Dahl salt-sensitive (SS) rats. We performed continuous assessment of mean arterial blood pressure (MAP) and renal blood flow (RBF) over a 2-wk period using radiotelemetry and ultrasound flow probes, respectively. In initial time control studies, we confirmed the stability of the surgical preparation in Sprague-Dawley rats. We next assessed MAP and RBF in male SS and SS^p67phox-/- during 2 wk of a high-salt (4.0% NaCl) diet. As we have previously shown, the hypertensive response to a high-salt diet was blunted in SS^p67phox-/- rats compared with SS rats. RBF increased significantly with a high salt in the SS^p67phox-/- rats. In contrast, although RBF was higher at baseline in SS rats than SS^p67phox-/- rats, there was no significant increase with high salt in the SS rats. Consequently, by the end of the 2-wk study, renal blood was equivalent in both groups. Using circadian analysis, we found that both MAP and RBF have circadian rhythms. These rhythms were not synchronous at baseline, with the nadir of RBF preceding that of MAP. This separation between rhythms was exacerbated by high salt. In conclusion, using chronic assessment of MAP and RBF, we have shown that when p67^phox is not functional in SS rats, high-salt causes a significant increase in RBF, and this is associated with a blunted hypertensive response. NEW & NOTEWORTHY Continuous measurements of MAP and RBF were made in conscious SS^p67phox-/- rats to determine the role of oxidative stress in their regulation. Deletion of p67^phox restored the vasodilatory response to a high-salt diet in SS rats. RBF increased in response to a salt load in SS^p67phox-/- but not SS rats. Circadian analysis demonstrated that MAP and RBF became asynchronous as the rats progressed through the high-salt challenge: RBF peaked over 4 h before MAP.

The (pro)renin receptor (PRR) is a multifunctional protein implicated in blood pressure regulation and kidney fibrosis. Previous studies report enhanced PRR expression in nondiabetic and diabetic kidney disease. In this study, we investigated whether deletion of renal tubular PRR attenuates kidney injury in type 2 diabetes. Floxed PRR mice were bred with mice expressing Pax8 rtTA and LC1 transgenes and db/db mice (B6.BKS) to obtain renal tubular PRR knockout (KO)-db/db mice. Male, age-matched nondiabetic floxed controls, db/db mice, and PRR KO-db/db mice were studied at 16, 20, 26, and 30 wk of age. PRR KO mice were only studied at 30 wk of age. To induce PRR deletion, PRR KO and PRR KO-db/db mice were treated with 2 mg/mL doxycycline for 12 days at 8-10 wk of age. Compared with controls, db/db mice and PRR KO-db/db mice had higher body weights throughout the study and elevated blood glucose levels at weeks 16 and 20. Compared with controls and db/db mice, PRR KO-db/db mice had higher urine volume, water intake, and urinary albumin excretion. At 30 wk, kidney histology showed minimal tubular or glomerular injury among all four groups. PRR KO mice had elevated expression of tubular injury markers compared with the other three groups. Plasma soluble PRR (sPRR) levels were almost twofold higher in diabetic mice relative to controls with no difference between db/db mice and PRR KO-db/db mice. Renal tubular deletion of PRR does not protect against kidney injury in type 2 diabetes; rather, the loss of PRR impairs baseline tubular function that is exacerbated by type 2 diabetes.NEW & NOTEWORTHY We investigated whether renal tubular deletion of the PRR would be protective in mice with type 2 diabetes. Longitudinal assessment to 30 wk of age demonstrated that diabetic mice with deletion of renal tubule PRR had higher albuminuria whereas gene expression of kidney injury markers was elevated in PRR KO mice at baseline compared with diabetic floxed controls and nondiabetic controls. Genetic deletion of PRR results in tubular cell dysfunction that is exacerbated by diabetes.

Aquaporins (AQPs) are a family of water channels found throughout the body and in the kidney; they function in maintaining water homeostasis. The insertion of AQPs into the plasma membrane of the kidney cells drives water reabsorption back into the circulation, and the concentration of the urine involves AQP2 apical localization in the collecting duct principal cells. Kidney functions, like glomerular filtration rate (GFR) and urine flow, are significantly greater during the active period compared with the inactive period when sleeping. We hypothesized that there is a diurnal pattern in urine and/or plasma osmolality and that this reflects changes in kidney aquaporins in mice. Male and female C57BL/6J mice were studied in the middle of their active period [zeitgeber time (ZT) 18] or the middle of their inactive period (ZT6). We confirmed GFR was greater at ZT18 compared with ZT6. Urine and plasma osmolality were significantly greater at ZT18 in both sexes. Although ∼18% of kidney RNA had a diurnal pattern, the changes observed in the Aqp genes did not reflect protein abundance differences where nephron AQP1, AQP2, and AQP4 abundance were greater at ZT18 compared with ZT6. In conclusion, diurnal variability in plasma osmolality and urine-concentrating ability is likely driven by time-of-day changes in intake, greater GFR, and establishment of the medullary interstitial gradient during the active period. Greater nephron aquaporins in the middle of the active period may function to reabsorb water while the kidney excretes excess solutes to dilute the plasma osmolality and maintain fluid-electrolyte balance.NEW & NOTEWORTHY Mouse plasma and urine osmolalities are greater in the middle of the active period, when food/water intake, gut reabsorption, glomerular filtration rate, and urine flow are increased. There were time-of-day effects on aquaporin mRNA, and increased nephron abundance of aquaporins during the middle of the active period. As the kidneys excrete the excess solutes, the medullary interstitial gradient and aquaporins are primed to concentrate the urine and return the plasma osmolality to a steady state.

Climate change has led to a rise in Vibrio vulnificus infections, while the global obesity epidemic has increased susceptibility to severe bacterial infections. Obesity and high-fat diet (HFD) consumption promote systemic inflammation and immune dysregulation, which may exacerbate sepsis and its complications, including acute kidney injury (AKI). This study investigates the mechanistic role of HFD-induced metabolic dysfunction in V. vulnificus sepsis-associated AKI. Adult C57BL/6J mice were placed on a standard CHOW diet or a 60% kcal HFD for 6 wk before infection. V. vulnificus infection was induced via intragastric administration by oral gavage of 10⁸ colony-forming units of V. vulnificus suspended in PBS. Kidney function was assessed, and kidney tissues were analyzed for markers of inflammation, oxidative stress, and necrosis. Systemic Th17/Treg ratios were determined. In vitro, renal proximal tubular epithelial cells were treated with leptin and IL-17A with/without an IL-17 receptor antagonist to confirm the role of IL-17 signaling in renal epithelial cell pathology. A proinflammatory Th17/Treg imbalance, along with a marked increase in renal TLR4 activation, inflammation, and necrosis, was observed in the HFD + Vibrio vulnificus infection group. In vitro studies confirmed that IL-17 and leptin synergistically activate the NF-κB pathway, promoting inflammatory cytokine release. These findings indicate that HFD-induced metabolic stress exacerbates V. vulnificus sepsis-associated AKI. The interplay between IL-17 signaling and leptin may further amplify renal injury, underscoring the need for targeted interventions. Strategies to modulate IL-17 signaling and metabolic inflammation may offer novel therapeutic approaches to reduce AKI severity in obese individuals with bacterial sepsis.NEW & NOTEWORTHY This study reveals that high-fat diet (HFD)-induced metabolic dysfunction exacerbates Vibrio vulnificus sepsis-associated acute kidney injury (AKI) via TLR4-driven inflammation, oxidative stress, and systemic Th17/Treg imbalance. Novel in vitro findings show that IL-17 and leptin synergistically activate NF-κB signaling in renal epithelial cells, amplifying inflammation, which is mitigated by IL-17 receptor blockade. These results highlight IL-17 signaling as a potential therapeutic target for reducing AKI severity in obese individuals with bacterial sepsis.

Hemorrhage and hypotension leading to renal hypoperfusion are common causes of acute kidney injury (AKI). Anesthetic agents may affect renal hemodynamics, potentially altering renal outcomes during hypovolemia. This study evaluated the effects of two commonly used anesthetics, propofol and sevoflurane, on renal blood flow (RBF) and oxygenation during hemorrhage. Fourteen pigs (30 ± 2 kg) were anesthetized with either propofol or sevoflurane, with fentanyl as an opioid supplement in both groups. Following baseline measurements, hemorrhage was induced to maintain a mean arterial pressure (MAP) below 50 mmHg for 30 min, after which resuscitation was performed using a 1:1 replacement of whole blood and Ringer's acetate. Acute renal function recovery was evaluated 1 h post resuscitation. At baseline, sevoflurane-anesthetized animals had lower RBF and renal oxygen delivery, and higher renal vascular resistance compared with the propofol group. During hemorrhage, the change in these variables was comparable. After resuscitation, cardiovascular and RBF recovery were similar between the groups. However, oxygen delivery remained significantly lower in the sevoflurane group compared with the propofol group. In addition, renal vascular resistance was significantly higher during sevoflurane anesthesia compared with propofol after recovery. In conclusion, compared with propofol anesthesia, sevoflurane anesthesia reduced RBF and renal oxygen delivery already at baseline. The difference in oxygen delivery persisted after hemorrhage, even though RBF was comparable between groups.NEW & NOTEWORTHY In a pig model of major hemorrhage, we investigated whether the choice of anesthetic agent impacts renal blood flow and oxygen delivery after hemorrhage. The volatile anesthetic sevoflurane reduced renal blood flow and oxygen delivery compared with the intravenous agent propofol before hemorrhage. Following hemorrhage, oxygen delivery remained lower, accompanied by sustained renal vasoconstriction, in subjects anesthetized with sevoflurane compared with those anesthetized with propofol.