Mesangial hypercellularity and excessive extracellular matrix (ECM) accumulation are defining lesions of mesangial proliferative glomerular diseases and drivers of progressive glomerulosclerosis and renal dysfunction. How mesangial cells (MCs) remain quiescent within the mechanically dynamic glomerular microenvironment, and why this control fails in disease, remain incompletely understood, in part because few in vitro systems combine three-dimensional (3-D) architecture, heterotypic cell interactions, and defined mechanical loading. We therefore developed a simplified three-dimensional (3-D) coculture system using immortalized mouse cell lines: MCs embedded in a type I collagen gel, overlaid with a monolayer of mouse microvascular endothelial cells and subjected to orbital shaking-induced fluid flow-derived mechanical loading, intended to model indirect loading rather than pressure-driven interstitial perfusion. In MC monoculture, fluid flow markedly increased MC expansion and Ki-67-positive cell density, whereas an overlying endothelial monolayer substantially attenuated this proliferative response under flow and reduced cleaved caspase-3-positive (CC3) apoptotic MCs. Endothelial coculture suppressed MC p38 MAPK and AKT phosphorylation under both static and fluid flow conditions, whereas flow increased ERK phosphorylation in the endothelial layer despite reduced total ERK abundance. Fluid flow enhanced MC collagen accumulation (Picrosirius Red staining), whereas endothelial coculture reduced total and type III collagen deposition under both conditions. These findings indicate that fluid flow and the endothelial monolayer are key determinants of the mesangial microenvironment, with flow prompting proliferation and the endothelium restraining proliferation and matrix deposition largely independently of flow. We propose that disruption of this endothelial-mesangial cross talk may contribute to the mesangial expansion and fibrosis of mesangial proliferative glomerulonephritis.NEW & NOTEWORTHY We established a three-dimensional (3-D) coculture model integrating fluid flow-derived mechanical loading, extracellular matrix architecture, and mesangial-endothelial interactions. Fluid flow intrinsically promoted MC expansion, whereas endothelial coculture robustly suppressed it. Thus, the endothelium restrains mesangial expansion through biological signaling rather than by physically shielding the matrix, whereas fluid flow reaches mesangial cells by enhancing convective solute transport rather than by direct mechanical loading, identifying endothelial signaling and flow-driven solute transport as regulators of the dynamic glomerular microenvironment.
Cisplatin is a widely used chemotherapeutic agent, but acute kidney injury (AKI) remains its dose-limiting toxicity, particularly in older patients. In recent years, dysregulated lipid metabolism has emerged as a key driver of cisplatin nephrotoxicity; however, the underlying mechanisms and their modulation across ages remain incompletely understood. Here, we demonstrated that the lipid droplet protein perilipin 2 (Plin2) was induced after cisplatin-induced AKI, with markedly greater induction in aged kidneys and distinct organ-specific patterns in the liver and heart. Knockdown of Plin2 protected against cisplatin-induced AKI in young mice, as evidenced by reduced serum creatinine and blood urea nitrogen levels, attenuated morphological injury, decreased tubular cell apoptosis, and diminished inflammation, but failed to confer protection in aged mice. Proteomic profiling identified selective upregulation of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2), suggesting enhanced ketogenesis in Plin2-knockdown kidneys. Surprisingly, Plin2 knockdown did not significantly alter fatty acid oxidation and glycolytic pathways after AKI. Mechanistically, Plin2 interacts with sirtuin 5 (Sirt5) to regulate Hmgcs2 desuccinylation, impairing ketogenesis and tubular energy homeostasis to exacerbate AKI in an age-dependent manner.NEW & NOTEWORTHY Aging is a major determinant of cisplatin nephrotoxicity, yet the mechanisms underlying age-dependent metabolic vulnerability remain unclear. This study revealed that lipid droplets are not merely lipid storage structures but actively regulate kidney metabolic adaptation during cisplatin-induced AKI. We identified Plin2 as a context-dependent regulator whose knockdown enhanced protective ketogenesis in young kidneys but lost efficacy with aging. These findings uncover age-dependent metabolic plasticity as a critical determinant of AKI susceptibility and therapeutic response.
Renal venous congestion is one of the most important hemodynamic factors driving renal dysfunction in patients with heart failure. However, the mechanisms whereby increases in renal venous pressure (RVP) impair renal function are not well understood. An anesthetized ovine model was used to test the hypothesis that elevations in RVP increase renal nerve activity and mediate impairments in renal hemodynamics and renal tissue oxygenation. The protocol was carried out in two groups: renal nerve intact (n = 8) and right unilateral renal denervated (n = 7) animals. During experimentally induced renal venous congestion, there was a significant increase in directly recorded renal nerve activity. RVP increases led to elevation-dependent increases in plasma renin activity, decreases in renal blood flow (RBF), renal vascular conductance (RVC), urine output, glomerular filtration rate (GFR), and renal medullary perfusion in both the intact and unilateral denervated groups. RVP increase had no significant effect on renal cortical perfusion in the intact group but markedly reduced cortical perfusion in the unilateral denervated group. Interestingly, there were no changes in renal medullary and cortical oxygenation during RVP elevation in the intact group, and reductions in these variables in the right unilateral renal denervated group. Our study provides direct evidence that renal venous congestion increases renal nerve activity and the renin-angiotensin system (RAS), impairs renal hemodynamics, and decreases GFR. The data during unilateral renal denervation suggest that the renal nerves do not regulate renal venous congestion-induced renal hemodynamic impairments. The nerves do play an important role in maintaining renal medullary tissue oxygenation.NEW & NOTEWORTHY Our study shows that renal venous congestion is not associated with an alteration in renal medullary oxygenation, although renal function is altered. Direct recordings of renal nerve activity indicate an elevation during renal venous congestion. The renal nerves do not regulate renal venous congestion-induced renal dysfunction since this is not different in a unilateral renal denervated group. The renal nerves exert a protective effect in maintaining renal medullary tissue oxygenation.
Ammonium excretion has been recognized for more than 100 yr as an integral component of renal maintenance of acid-base homeostasis. However, whether ammonium excretion directly contributes to net acid excretion or whether it is a marker of proximal tubule glutamine-derived bicarbonate generation has not been directly determined. The current studies use mice with a proximal tubule (PT)-specific deletion of phosphoenolpyruvate carboxykinase-knockout (PT-PEPCK-KO) to address this question. Although on a control diet, PT-PEPCK-KO mice exhibited an approximately four times increase in urine ammonia excretion, in association with increased urine acidification, yet had significantly lower serum bicarbonate levels. Acid-loading, with a protocol providing only 25% of our standard acid load, increased ammonium excretion in both wild-type (WT) and knockout (KO) mice, but to a greater extent in KO mice. Despite the increased ammonium excretion, serum bicarbonate decreased in KO mice compared with mice on a control diet, whereas WT mice exhibited no significant change. Phosphate-dependent glutaminase expression was greater in KO mice than WT mice, both on a control diet and after acid loading. Expression of glutamine synthetase, a PT ammonium-recycling enzyme, was decreased in PT-PEPCK-KO mice on both control and acid-loading diets. As PEPCK deletion blocks glutamine-derived bicarbonate generation, but not ammonium generation and excretion, we conclude that ammonium generation and excretion do not significantly contribute to acid-base homeostasis and instead serve primarily as a marker of PT-derived bicarbonate generation.NEW & NOTEWORTHY These studies show that renal ammonium generation and excretion are not a direct method of acid-base homeostasis. Instead, they show that urinary ammonium excretion functions in acid-base homeostasis as a marker of proximal tubule new bicarbonate generation.
The renal distal convoluted tubule (DCT) plays a key role in magnesium homeostasis, with genetic and drug-induced causes of hypomagnesemia affecting this segment. The importance of the renal transient receptor potential melastatin (TRPM) 6 channel subunit of the TRPM6/7 magnesium channel in magnesium homeostasis is unclear due to discrepant findings in knockout mice. Furthermore, the apical voltage-gated potassium channel subtype 1.1 (Kv1.1) has been proposed to drive magnesium entry through TRPM6/7 along DCT, with limited experimental evidence. To clarify the roles of TRPM6 and Kv1.1, we generated mice with inducible DCT-specific TRPM6 knockout (DCT-TRPM6 KO) or renal tubule Kv1.1 knockout (tubule-Kv1.1 KO). Using a newly generated antibody, we found that TRPM6 expression is restricted to early DCT (DCT1), consistent with single-cell transcriptomic data. DCT-TRPM6 KO displayed lower plasma [Mg2+] on diets with normal (0.21% wt/wt) or reduced (0.08% wt/wt) magnesium content. In contrast, plasma [Mg2+] did not differ from controls in tubule-Kv1.1 KO mice on diets containing 0.08% wt/wt or 0.04% wt/wt magnesium. There were no differences in other blood chemistry values for either knockout. Glomerular filtration rate (GFR), lithium clearance, and natriuretic responses to furosemide, hydrochlorothiazide, or amiloride did not differ in tubule-Kv1.1 KO mice. Immunofluorescence and single-molecule fluorescent in situ hybridization revealed Kv1.1 expression in mouse and human glomeruli and along the S3 segment of the proximal tubule, but not along DCT. In summary, renal TRPM6 plays a critical role in magnesium homeostasis under baseline conditions. Kv1.1 is not expressed along DCT and is not required for magnesium homeostasis or normal renal function at baseline.NEW & NOTEWORTHY Using DCT-specific TRPM6 and renal tubule Kv1.1 knockout mice, we found that TRPM6, but not Kv1.1, is expressed in DCT and is required to maintain plasma [Mg2+]. In mouse and human kidney, Kv1.1 is expressed in glomerular epithelia and the S3 segment of the proximal tubule. Renal tubule disruption of Kv1.1 did not affect blood chemistry, GFR, lithium clearance, or diuretic responses at baseline. Our data clarify the roles of these channels in the kidney.
Ferritin dysregulation is implicated in numerous pathological conditions; however, its role in autosomal dominant polycystic kidney disease (PKD) remains poorly understood. Ferritin expression is increased in cyst-lining epithelial cells and macrophages in both PKD mouse and human kidneys. To investigate the functional significance of ferritin/iron homeostasis in disease progression, we generated conditional knockout of ferritin heavy chain (FTH) in collecting duct or myeloid lineage cells of PKD mice. FTH deletion in either cell type did not impact renal cyst growth. Notably, loss of FTH expression was accompanied by compensatory upregulation of ferritin light chain (FTL) in both models. To assess the effects of systemic ferritin infusion, we administered ferritin (iron replete), apoferritin (iron deplete), or phosphate-buffered saline (PBS; vehicle control) to PKD mice. Ferritin but not apoferritin infusion led to splenomegaly in wild-type (WT) and PKD mice, with no obvious alterations in cyst progression. Notably, ferritin infusion led to focal accumulation of ferritin in macrophage-enriched regions within the kidneys of PKD, but not WT mice. Consistent with this, elevated iron was detected in the kidneys of ferritin-treated PKD mice but not in wild-type controls, suggesting dysfunctional ferritin trafficking. Mechanistically, we observed increased uptake of ferritin and dysregulation of ferritin receptors by renal cystic epithelial cells of PKD patients. Ferritin-enriched areas were positive for heme oxygenase 1 and represented high oxidative stress and fibrosis. Collectively, these findings demonstrate a disruption in ferritin handling and iron homeostasis in PKD. This altered iron trafficking promotes localized oxidative stress and fibrosis, contributing to disease progression.NEW & NOTEWORTHY Ferritin dysregulation in autosomal dominant polycystic kidney disease (ADPKD) reveals a novel disease mechanism. Although ferritin heavy chain deletion does not affect cyst growth, polycystic kidney disease (PKD) kidneys show compensatory ferritin light chain upregulation and abnormal ferritin trafficking. Iron-loaded ferritin accumulates in macrophage-rich regions, increasing oxidative stress and fibrosis. Enhanced ferritin uptake and receptor dysregulation in cystic epithelial cells highlight disrupted iron homeostasis as a previously unrecognized contributor to ADPKD progression.
Cardiovascular (CV) disease remains the leading cause of death worldwide, with metabolic disorders nearly doubling CV risk mortality. Although adult lifestyle factors contribute to disease development, increasing evidence supports a critical role for developmental programming in shaping the long-term cardiac health. The developmental origins of health and disease concept, first proposed by Barker, associates low birth weight with increased CV risk in adulthood. Subsequent studies demonstrated that maternal health, including undernutrition, smoking, preeclampsia (PE), autoimmune diseases, and polyendocrine metabolic ovarian syndrome (PMOS), is associated with impaired fetal growth and increased susceptibility to CV, renal, and metabolic disease in offspring. Conversely, high birth weight, associated with maternal or parental obesity, is linked to elevated risk of obesity, type 2 diabetes, renal susceptibility, and heart failure later in life. Preclinical models of developmental insults identify key mechanistic pathways, including activation of the renin-angiotensin system, sympathetic nervous system, oxidative stress, and immune dysregulation, with additional sex-specific differences in susceptibility to adverse outcomes after injury. Despite advances, preventive strategies targeting the preconception and gestational periods remain limited. This review highlights mechanisms linking impaired fetal growth induced via developmental exposure to PE, PMOS, maternal obesity, and parental obesity to long-term cardiometabolic and renal risk and discusses emerging therapeutic approaches.
It is unclear whether the reported natriuretic and diuretic effects of glucagon are mediated by renal hemodynamic changes or by direct tubular actions within the kidney. We investigated the renal effects of acute glucagon infusion in rats. We further examined whether these effects are mediated by activation of the glucagon receptor (GCGR) or whether the glucagon-like peptide-1 receptor (GLP-1R) also contributes. Experiments were performed in Sprague-Dawley rats and spontaneously hypertensive rats. Animals received glucagon infusion alone or with selective receptor antagonists targeting GCGR (GRA) or GLP-1R (Exendin9-39). Renal hemodynamics, urine flow, and electrolyte excretion were assessed. Acute glucagon infusion consistently increased urinary sodium excretion and urine flow across all experimental groups, whereas renal blood flow did not change significantly. Urinary osmolality decreased in parallel with increased sodium and water excretion, and free water clearance remained negative despite increased urine flow, indicating solute-driven diuresis rather than antidiuretic hormone suppression. Receptor antagonist experiments demonstrated that blockade of either GCGR or GLP-1R partially attenuated the glucagon-induced renal responses. In conclusion, acute glucagon infusion induces natriuresis and diuresis primarily through a direct tubular mechanism, largely independent of renal hemodynamic changes. These effects are mediated by multiple overlapping receptor pathways, as neither GCGR nor GLP-1R blockade alone was sufficient to abolish the response, and their relative contributions may vary depending on physiological context. These findings may be relevant for understanding the renal effects of emerging glucagon-based therapies, including dual GLP-1/glucagon and triple GLP-1/GIP/glucagon receptor co-agonists, where overlapping receptor activation could influence renal sodium handling.
Cisplatin is a widely used chemotherapeutic agent whose nephrotoxicity limits its clinical utility. Here, we investigated whether thermal therapy alleviates cisplatin-induced injury in renal proximal tubular epithelial cells (NRK52E) and explored the underlying molecular mechanisms. Although simultaneous thermal stimulation with cisplatin showed no protective effect, thermal preconditioning (TP) performed 6 h prior exerted significant cytoprotection. This effect was mediated by early TRP vanilloid 4 (TRPV4) activation, which triggered enhanced Ca2+ influx and subsequent upregulation of heat shock protein 27 (HSP27), a cytoprotective chaperone. Inhibition or knockdown of TRPV4 or HSP27 abolished the protective effects, confirming their essential roles. These findings suggest that TP induces a preemptive protective response in renal tubular cells, highlighting TRPV4-mediated HSP27 expression as a key mechanism for reducing cisplatin nephrotoxicity.NEW & NOTEWORTHY Thermal preconditioning (TP) performed 6 h before cisplatin exposure protected against cisplatin-induced tubular injury, unlike simultaneous heating. TP activated TRPV4 channels, inducing Ca2+ influx and upregulating the cytoprotective chaperone HSP27. Inhibition or knockdown of TRPV4 or HSP27 abolished this protection, confirming their critical roles. These results indicate that TRPV4-mediated HSP27 induction is a key mechanism by which TP elicits preemptive defense against cisplatin-induced nephrotoxicity.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that occurs more frequently in women and is associated with an increased risk of renal injury and hypertension. Studies have shown that obesity is associated with greater SLE disease activity and is a significant modifiable risk factor for hypertension. Although dietary interventions such as vitamin D supplementation, omega-3 fatty acids, and macronutrient modification have been tested in autoimmune disease, little is known about how diet influences blood pressure (BP) in the setting of SLE. Caloric restriction (CR) has been shown to extend lifespan, delay nephritis, and reduce autoantibody production in murine models of SLE. However, its impact on hypertension and renal outcomes is poorly understood. In this study, we hypothesized that CR would ameliorate hypertension and renal injury in NZBWF1 mice, an established model of SLE. Female NZBWF1 and NZW control mice were subject to ad libitum (ADL) or 30% CR feeding for 8 wk. CR mice had reduced body weight (BW), plasma leptin levels, and autoantibody levels. CR mice also exhibited decreased albuminuria, urinary kidney injury molecule-1 (KIM-1), and renal B and T cell infiltration. CR mice had lower blood pressure, and the lower BP in SLE-CR mice neared significance in comparison to SLE-ADL. These findings demonstrate that CR tends to lower blood pressure and improves renal injury in NZBWF1 mice. Together, these results highlight the interplay between metabolic status, immune dysregulation, and renal complications in SLE, suggesting that CR may be a promising approach to mitigate end-organ damage in SLE-associated hypertension.NEW & NOTEWORTHY Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that primarily affects women and is associated with high rates of hypertension and obesity. This study tested the hypothesis that caloric restriction would decrease disease activity and lower blood pressure in the NZBWF1 mouse, an obese and hypertensive model of SLE. Caloric restriction mice had decreased SLE disease activity, with lower anti-dsDNA IgG autoantibodies, albuminuria, renal B and T cell infiltration, and blood pressure.
Polycystic kidney disease (PKD) is a common hereditary kidney disorder with an insidious onset and complex mechanisms, making early diagnosis challenging. Current diagnostic methods, including imaging and genetic testing, have limitations. Imaging detects cysts only once formed, and genetic testing is costly, labor-intensive, and unable to guarantee complete diagnostic accuracy or predict onset and progression. Metabolomics may offer an approach to uncover PKD mechanisms by detecting metabolic alterations that precede clinical manifestations, enabling identification of disease-specific biomarkers, and providing earlier and more practical detection than imaging or genetic testing. This review synthesizes existing metabolomics studies of human PKD and renal cystic disease with significant metabolites extracted and pathway enrichment analyses conducted at the levels of overall cystic kidney disease and the autosomal dominant polycystic kidney disease (ADPKD)/Pkd1/non-Pkd1 subsets to identify significant pathways and their associated metabolic features. Overall, the top-ranked pathways were arginine biosynthesis; alanine, aspartate, and glutamate metabolism; glycine, serine, and threonine metabolism; and the citrate cycle, with glycine, serine, and threonine metabolism only associated with ADPKD/Pkd1 mouse models. These pathways indicate marked activation of amino acid metabolism accompanied by relative suppression of carbohydrate-related energy metabolism, suggesting a shift in metabolic substrate utilization rather than a complete loss of energy supply. This study provides a foundation for applying metabolomics to early diagnosis and mechanistic investigation of cystic kidney disease.
Smartwatches are widely used by the general population as tools to promote wellness. Modern smartwatches can monitor arterial oxygen saturation, blood pressure, heart rate, arrhythmias, physical activity, sleep patterns, falls, and body composition. In individuals with chronic illnesses, smartwatches may support improved self-care and patient empowerment, support advanced phenotyping by providing digital biomarkers, enable early detection of clinically relevant changes in physiological parameters, and facilitate remote patient monitoring. Patients with chronic kidney disease, particularly those with kidney failure, often experience multiple abnormalities in physiological parameters and body functions. These disturbances may go undetected during routine clinical visits or hemodialysis (HD) treatments, yet they can significantly impact outcomes and may be amendable through therapeutic interventions. Especially when integrated with data from electronic health records and medical devices such as HD machines, smartwatches may be part of a digital ecosystem, supporting personalized precision care and patient empowerment. However, the use of smartwatches in healthcare can also produce false positive signals, which can lead to patient anxiety and potentially increase healthcare utilization and contribute to digital inequity. At present, the potential and challenges of smartwatches in kidney disease are largely unexplored. To fill this gap, this review aims to provide a comprehensive overview of smartwatch-based applications in health monitoring, highlighting both opportunities and limitations in patients with chronic kidney disease and kidney failure. Despite promises for future healthcare implementation, the lack of validation studies for clinical-grade measurements presently still precludes the use of smartwatches for clinical decision-making.
Persistent and repeated damage contribute to chronic kidney disease (CKD) progression, with repair responses diverging between successful resolution and failed repair. In the transition towards failed repair, renal tubules develop a maladaptive phenotype which establishes conditions that sustain chronic inflammation leading to fibrosis. To define regulators of this inflection point, we investigated the role of non-canonical NF-B signaling, a persistent inflammatory pathway that is activated under chronic stress. Using CRISPR-Cas9 gene editing, we generated a novel Fn14 knockout (Fn14-KO) mouse, as Fn14 is one of a limited number of receptors identified that engages the non-canonical NF-B pathway. Male and female wildtype and Fn14-KO mice underwent a repeated low-dose cisplatin regimen to model CKD. Post-treatment, we analyzed blood biochemistry, renal histopathology, and renal gene expression via the NanoString nCounter platform. Although renal injury was observed by histology and gene expression (KIM-1) in both wildtype and Fn14-KO mice following cisplatin treatment, transcriptional profiles suggested that Fn14-KO mice exhibited relative preservation of proximal tubule differentiation and survival markers. In contrast, wildtype kidneys displayed hallmark transcriptional features of maladaptive repair, including tubular dedifferentiation, apoptosis, complement activation, and fibrogenesis. Collectively, these findings suggest that Fn14-mediated non-canonical NF-B signaling is a critical driver of the transition to maladaptive repair, positioning it as a potential therapeutic target to mitigate CKD progression.
Mutations in the Na+/[Formula: see text] cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA) and extrarenal symptoms including glaucoma, band keratopathy, migraine, growth disorder, and abnormal tooth enamel. From the NCBI dbSNP database, we recently identified a previously uncharacterized single-nucleotide variant (SNV), R881S, in NBCe1, located in hydrophilic helix 4. R881S NBCe1-A showed intracellular retention in human embryonic kidney 293 (HEK293) cells, and its plasma membrane expression was profoundly reduced in polarized Madin-Darby carine kidney (MDCK) cells. Unlike wild-type (WT) and R881C NBCe1-A (which causes pRTA), Western blot analysis demonstrated that the R881S NBCe1-A showed a single, low-molecular-weight signal above 100 kDa. Deglycosylation study showed that R881S NBCe1-A was scarcely deglycosylated by PNGase F. Coimmunoprecipitation study demonstrated that wild-type and R881S NBCe1-A did not form a heterodimer. Moreover, functional analysis using Xenopus oocytes revealed that the R881S variant had markedly reduced transport activity compared with wild-type NBCe1-A. Thus, R881S NBCe1-A shows no detectable transport activity, likely due to defective trafficking and reduced glycosylation. In contrast to the R881C mutant, however, R881S NBCe1-A fails to form dimers with wild-type NBCe1-A, suggesting the absence of a dominant-negative effect and underscoring the need for functional characterization of reported genetic variants.NEW & NOTEWORTHY Electrogenic Na+/[Formula: see text] cotransporter 1-A (NBCe1-A) in the proximal tubules regulates acid/base balance and fluid volume homeostasis. From the NCBI dbSNP database, we identified R881S NBCe1-A, which lacks glycosylation, cell-surface expression, and transport activity. We also found that the R881S variant does not form heterodimers with wild type, likely due to a reduced opportunity to interact with the wild-type protein at the plasma membrane.
Low sexual function is common in chronic kidney disease (CKD), yet the contribution of inflammatory pathways in affected women remains poorly defined. We sought to characterize cytokine profiles associated with low sexual function in women with advanced CKD. We enrolled 32 women aged 18-51 yr with CKD stages 3b-5 in a cross-sectional study assessing hormonal profiles and sexual function using the Female Sexual Function Index (FSFI); low sexual function was defined as FSFI <26.55. Plasma samples were analyzed using a 48-plex cytokine assay. Cytokine concentrations were compared using the Wilcoxon two-sample test, with false discovery rate control (FDR <0.05) via the Benjamin-Hochberg procedure. Principal component analysis (PCA) was used to evaluate cytokine patterns associated with low sexual function. : Thirty participants completed the FSFI; 22 (73%) met criteria for low sexual function. Of 48 cytokines examined, soluble CD40 ligand (sCD40L) was the only marker that remained significant after FDR correction, with lower levels observed in women with low sexual function (median 520.9 vs. 1,140 pg/mL; P = 0.0004; FDR = 0.02). Each 100 pg/mL increase in sCD40L was associated with a 34% reduction in odds of having low sexual function after adjusting for age and estimated glomerular filtration rate [adjusted odds ratio (OR) 0.66; 95% confidence interval (CI) 0.49-0.90]. PCA revealed that principal component 1 explained 37.4% of the variance, and higher levels were associated with a higher odds of low sexual function (OR 1.42; 95% CI 1.03-1.96). Low sexual function was highly prevalent and associated with differences in inflammatory and immune signaling, suggesting immune-vascular pathways may influence female sexual health in CKD.NEW & NOTEWORTHY This study is the first to investigate cytokine profiles in women with advanced CKD and low sexual function. We found that lower levels of soluble CD40 ligand were independently linked to higher odds of having low sexual function. Principal component analysis demonstrated that a broader immune activation pattern was associated with higher odds of having low sexual function. Together, these findings suggest that immune signaling patterns may be relevant to sexual health in women with CKD.
The renin-angiotensin-aldosterone system (RAAS) is essential in controlling fluid balance and blood pressure. In salt-sensitive (SS) hypertension, circulating RAAS is overactive, and the renin response to changes in sodium intake is bidirectionally blunted. Here, we used wild-type Dahl SS rats and renin knockout rats on the Dahl SS background (SSren-/-) to understand the role of renin in blood pressure regulation under salt-deficient (SD; 0.01% NaCl) and high-salt (HS; 4% NaCl) diets. We hypothesized that, compared with SSWT rats, SSren-/- rats would have lower blood pressure on the SD diet due to underdeveloped medulla and would return to normal blood pressure on the HS diet. First, we examined circulating RAAS after 10 days of SD and HS diets in SSWT rats. A 10-day SD diet robustly activated all parts of the circulating RAAS in Dahl SS rats, whereas a 10-day HS diet significantly decreased the aldosterone-to-Ang II ratio. In addition, we measured mean arterial blood pressure, glomerular filtration rate, urine output, and blood and urine electrolyte levels in SSren-/- rats and SSWT rats (littermates) under normal salt (NS; 0.4% NaCl) and after 10 days of SD or HS diets. SD feeding significantly reduced the blood pressure, plasma Na+, and Cl- of SSren-/- rats. HS diet caused a rapid rise in blood pressure, with 100% mortality in SSren-/- rats. In summary, these findings demonstrate that loss of renin impairs adaptive responses to dietary salt, and proper RAAS function is vital for maintaining blood pressure in salt-sensitive hypertension.NEW & NOTEWORTHY A 10-day high-salt diet caused a rapid increase in blood pressure and 100% mortality in renin-deficient Dahl salt-sensitive rats, demonstrating that intact renin-angiotensin-aldosterone system (RAAS) signaling is essential for blood pressure regulation in salt-sensitive hypertension.
Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. STCs may be damaged and rendered ineffective by renovascular disease (RVD), but the underlying mechanisms remain unknown. We hypothesized that RVD induces changes in methylated (5mC) and hydroxymethylated (5hmC) DNA and modulates the transcriptomic profile and functional properties of swine STCs. CD24+/CD133+ STCs were harvested from pig kidneys after 10 wk of RVD or sham (n = 6 each), and their 5mC and 5hmC profiles of individual peaks were examined by immunoprecipitation sequencing (MeDIP-/hMeDIP-seq, respectively, n = 3 each). Integrated (MeDIP/hMeDIPseq/mRNA-seq) analysis was performed, followed by functional analysis of overlapping differentially expressed (DE) genes. STC-protective effects were assessed in vitro before and after epigenetic (Bobcat339) modulation. MeDIP-seq analysis identified 1,362 hypermethylated and 1,432 hypomethylated peaks in RVD-STCs compared with Normal-STCs, which correlated with 80 upregulated and 55 downregulated genes in RVD-STCs. hMeDIP-seq revealed 1,447 hyper-hydroxymethylated and 765 hypo-hydroxymethylated peaks in RVD-STCs vs. Normal-STCs, which correlated with 80 genes upregulated and 53 downregulated in RVD-STCs. Overlapping upregulated genes were mainly implicated in the regulation of oxidative phosphorylation, apoptosis, and lipid metabolism (e.g., STAT6), whereas overlapping downregulated genes were mainly involved in cell proliferation. Importantly, RVD increased STAT6 protein expression and impaired the proliferative capacity of STCs, which were partially reversed by treatment with Bobcat339, which also enhanced the ability of RVD-STCs to promote the viability of injured tubular epithelial cells. Renal ischemia induces locus-specific epigenetic alterations, associated with transcriptomic changes and impaired reparative function of swine STCs. These observations may contribute to developing novel approaches to preserve the reparative capacity of STCs in individuals with RVD.NEW & NOTEWORTHY Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.
Cardiac surgery-associated acute kidney injury (CS-AKI) occurs in 20–30% of patients undergoing cardiac surgery and is associated with poor prognosis and increased healthcare burden. Despite its clinical importance, effective preventive strategies remain lacking due to the complex and poorly understood mechanisms involved. Nitrite, a nitric oxide donor active under hypoxic conditions, has shown organ-protective effects in preclinical studies, but its role in CS-AKI has not been investigated. In this study, we developed a rat model of cardiopulmonary bypass induced AKI and found that inflammation-related pathways, including TNF and NFκB signaling, were prominently activated. Pre-treatment with nitrite significantly reduced the expression of kidney injury markers and attenuated the activation of inflammation-related gene pathways. These findings highlight the contribution of inflammation to CS-AKI and suggest the therapeutic potential of nitrite for protecting kidney function during cardiac surgery.
Brain death (BD) induces a robust inflammatory response that impairs kidney quality before transplantation. Given that TNFα is a central upstream mediator of BD-related injury, we investigated whether selective TNFα inhibition using etanercept could mitigate renal damage in a rat model of BD. BD was maintained for 6 h in anesthetized rats (n = 6 controls; n = 12 etanercept-treated; balanced for sex), after which animals were randomized to receive either etanercept (ETNCPT) or vehicle (CTL). We evaluated serum biomarkers, histological kidney injury, immune cell infiltration, and whole-kidney transcriptomic profiles. Etanercept significantly reduced circulating TNFα levels (15.25 [12.30-21.05] vs. 34.23 [26.03-50.19] pg/mL; P < 0.001), whereas other cytokines remained unchanged. Kidney function parameters [serum creatinine and blood urea nitrogen (BUN)], electrolytes, and hemodynamics were similar across groups. In contrast, etanercept markedly attenuated renal injury, reducing acute tubular necrosis (30.0 [15.0-35.0]% vs. 42.5 [40.0-51.3]%; P < 0.001), CD11b+ myeloid infiltration (0.13 [0.11-0.15]% vs. 0.21 [0.19-0.27]%; P < 0.001), tubular kidney injury molecule-1 expression (0.04 [0.01-0.08]% vs. 0.17 [0.13-0.18]%; P < 0.001), and apoptosis (-69%; P = 0.036). Transcriptomic analysis identified 281 differentially expressed genes after TNFα blockade, with strong inhibition of inflammatory and apoptotic pathways including TNF signaling, TNFR1/TNFR2 activation, death receptor signaling, and cytokine storm signaling. Predicted downstream effects included reduced kidney cell death and inflammation. Sex-stratified analyses showed similar directional effects in males and females. In summary, early TNFα blockade after BD selectively neutralizes TNFα, limits immune recruitment, and suppresses injury and inflammatory signaling at cellular and transcriptomic levels. Targeting TNFα during kidney donor management may offer a promising strategy to improve kidney quality before transplantation.NEW & NOTEWORTHY Brain death (BD) remains a major contributor to kidney injury in deceased donors. In this study, we demonstrate that selective TNFα blockade with etanercept during donor management markedly reduces BD-induced renal damage. Using a rat model of 6-h BD, we show that etanercept selectively neutralizes circulating TNFα without altering hemodynamics or kidney function markers yet significantly decreases tubular injury, myeloid infiltration, KIM-1 expression, and apoptosis. Whole-kidney transcriptomics confirmed broad suppression of TNF-dependent inflammatory and apoptotic pathways. These findings confirm TNFα as a central mediator of BD-associated renal injury and support TNFα-targeted interventions as a promising strategy to improve the quality of BD donor kidney before transplantation.
We present the experimental results on electron-beam deposition of Y2O3-stabilized zirconium dioxide ceramic coatings using a fore vacuum plasma-cathode electron source. The influence of the substrate roughness on the structure and roughness of the coating was evaluated. It was found that, at the roughness of the substrate Ra 1.96-0.21 microns, the coatings have the best adhesive properties. Coatings are subject to destruction due to inelastic deformation and mechanical coupling with the substrate.
