Chlorogenic acid alleviate kidney fibrosis through regulating TLR4/NF-қB mediated oxidative stress and inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Chlorogenic acid (CGA), a phenolic acid produced by the interaction of Caffeic acid and Quinic acid, is considered to be the main active ingredient in many heat-clearing and detoxifying Chinese medicines, such as honeysuckle, Houttuynia, Artemisia annua, Gardenia, etc. CGA has anti-inflammatory, antioxidant, anticancer, antibacterial and other properties. However, the effect and process of CGA in kidney fibrosis remain unknown. AIM OF THE STUDY: To investigate the therapeutic effects of CGA on alleviating kidney fibrosis and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 mouse kidney fibrosis model was established by unilateral uretera obstruction (UUO), followed by treatment with CGA (40, 80 mg/kg/d) for 10 days. The serum and kidney tissue were collected. Network pharmacology, molecular docking and transcriptomic analysis were conducted to explore the possible mechanisms. The HK-2 cells were cultured and treated with TGF-ß1(10 ng/mL) and CGA (50, 100 µM), to examine the role of TLR4/NF-қB signaling pathway in the therapeutic effect of CGA on kidney fibrosis. RESULTS: CGA significantly alleviated kidney injury, inflammation, oxidative stress and fibrosis in UUO models. CGA also effectively inhibited the expression of inflammatory factors and the process of oxidative stress both in vivo and in vitro fibrosis models. Further, transcriptomic analysis, molecular docking, and network pharmacology results indicated that the therapeutic effect of CGA on fibrosis was through the regulation of TLR4/NF-қB signaling pathway. CONCLUSION: CGA might provide benefits for the regulation of inflammatory response, oxidative stress and fibrogenesis by modulating TLR4/NF-қB signaling pathway on kidney fibrosis. Hence, CGA is an attractive agent for treating kidney fibrosis. The present study provided a basis for further research on the therapeutic strategies of kidney fibrosis.

Targeted Drug Therapy for Senescent Cells Alleviates Unilateral Ureteral Obstruction-Induced Renal Injury in Rats.

Hydronephrosis resulting from unilateral ureteral obstruction (UUO) is a common cause of renal injury, often progressing to late-stage renal fibrosis or even potential renal failure. Renal injury and repair processes are accompanied by changes in cellular senescence phenotypes. However, the mechanism is poorly understood. The purpose of this study is to clarify the changes in senescence phenotype at different time points in renal disease caused by UUO and to further investigate whether eliminating senescent cells using the anti-senescence drug ABT263 could attenuate UUO-induced renal disease. Specifically, renal tissues were collected from established UUO rat models on days 1, 2, 7, and 14. The extent of renal tissue injury and fibrosis in rats was assessed using histological examination, serum creatinine, and blood urea nitrogen levels. The apoptotic and proliferative capacities of renal tissues and phenotypic changes in cellular senescence were evaluated. After the intervention of the anti-senescence drug ABT263, the cellular senescence as well as tissue damage changes were re-assessed. We found that before the drug intervention, the UUO rats showed significantly declined renal function, accompanied by renal tubular injury, increased inflammatory response, and oxidative stress, alongside aggravated cellular senescence. Meanwhile, after the treatment with ABT263, the rats had a significantly lower number of senescent cells, attenuated renal tubular injury and apoptosis, enhanced proliferation, reduced oxidative stress and inflammation, improved renal function, and markedly inhibited fibrosis. This suggests that the use of the anti-senescence drug ABT263 to eliminate senescent cells can effectively attenuate UUO-induced renal injury. This highlights the critical role of cellular senescence in the transformation of acute injury into chronic fibrosis.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway.

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-ß1 (TGF-ß1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.

Kangxianling formula attenuates renal fibrosis by regulating gut microbiota.

BACKGROUND: Renal fibrosis (RF) produced adverse effect on kidney function. Recently, intestinal dysbiosis is a key regulator that promotes the formation of renal fibrosis. This study will focus on exploring the protective mechanism of Kangxianling Formula (KXL) on renal fibrosis from the perspective of intestinal flora. METHODS: Unilateral Ureteral Obstruction (UUO) was used to construct rats' model with RF, and receive KXL formula intervention for 1 week. The renal function indicators were measured. Hematoxylin-eosin (HE), Masson and Sirus red staining were employed to detect the pathological changes of renal tissue in each group. The expression of α-SMA, Col-III, TGF-ß, FN, ZO-1, and Occuludin was detected by immunofluorescence and immunohistochemistry. Rat feces samples were collected and analyzed for species' diversity using high-throughput sequencing 16S rRNA. RESULTS: Rats in UUO groups displayed poor renal function as well as severe RF. The pro-fibrotic protein expression in renal tissues including α-SMA, Col-III, TGF-ß and FN was increased in UUO rats, while ZO-1 and Occuludin -1 expression was downregulated in colon tissues. The above changes were attenuated by KXL treatment. 16S rRNA sequencing results revealed that compared with the sham group, the increased abundance of pathogenic bacteria including Acinetobacter, Enterobacter and Proteobacteria and the decreased abundance of beneficial bacteria including Actinobacteriota, Bifidobacteriales, Prevotellaceae, and Lactobacillus were found in UUO group. After the administration of KXL, the growth of potential pathogenic bacteria was reduced and the abundance of beneficial bacteria was enhanced. CONCLUSION: KXL displays a therapeutical potential in protecting renal function and inhibiting RF, and its mechanism of action may be associated with regulating intestinal microbiota.

Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury.

The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell overproliferation, tubular injury, and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistent with this, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell overproliferation, tubular injury, and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, where tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell overproliferation, tubular injury, and renal inflammation.

Diosmin ameliorates renal fibrosis through inhibition of inflammation by regulating SIRT3-mediated NF-κB p65 nuclear translocation.

BACKGROUND: Renal fibrosis is considered an irreversible pathological process and the ultimate common pathway for the development of all types of chronic kidney diseases and renal failure. Diosmin is a natural flavonoid glycoside that has antioxidant, anti-inflammatory, and antifibrotic activities. However, whether Diosmin protects kidneys by inhibiting renal fibrosis is unknown. We aimed to investigate the role of Diosmin in renal interstitial fibrosis and to explore the underlying mechanisms. METHODS: The UUO mouse model was established and gavaged with Diosmin (50 mg/kg·d and 100 mg/kg·d) for 14 days. HE staining, Masson staining, immunohistochemistry, western blotting and PCR were used to assess renal tissue injury and fibrosis. Elisa kits were used to detect the expression levels of IL-1ß, IL-6, and TNF-α and the activity of SIRT3 in renal tissues. In addition, enrichment maps of RNA sequencing analyzed changes in signaling pathways. In vitro, human renal tubular epithelial cells (HK-2) were stimulated with TGF-ß1 and then treated with diosmin (75 µM). The protein and mRNA expression levels of SIRT3 were detected in the cells. In addition, 3-TYP (selective inhibitor of SIRT3) and SIRT3 small interfering RNA (siRNA) were used to reduce SIRT3 levels in HK-2. RESULTS: Diosmin attenuated UUO-induced renal fibrosis and TGF-ß1-induced HK-2 fibrosis. In addition, Diosmin reduced IL-1ß, IL-6, and TNF-α levels in kidney tissues and supernatants of HK-2 medium. Interestingly, Diosmin administration increased the enzymatic activity of SIRT3 in UUO kidneys. In addition, Diosmin significantly increased mRNA and protein expression of SIRT3 in vitro and in vivo. Inhibition of SIRT3 expression using 3-TYP or SIRT3 siRNA abolished the anti-inflammatory effects of diosmin in HK-2 cells. Enrichment map analysis by RNA sequencing indicates that the nuclear factor-kappa B (NF-κB) signaling pathway was inhibited in the Diosmin intervention group. Furthermore, we found that TGF-ß1 increased the nuclear expression of nuclear NF-κB p65 but had little significant effect on the total intracellular expression of NF-κB p65. Additionally, Diosmin reduced TGF-ß1-caused NF-κB p65 nuclear translocation. Knockdown of SIRT3 expression by SIRT3 siRNA increased the nuclear expression of NF-κB p65 and abolished the inhibition effect of Diosmin in NF-κB p65 expression. CONCLUSIONS: Diosmin reduces renal inflammation and fibrosis, which is contributed by inhibiting nuclear translocation of NF-κB P65 through activating SIRT3.

Is lower fetal heart rate variability a susceptibility marker to the impact of negative coparenting on infant regulatory capacity?

Lower fetal heart rate variability (FHRV) may be a prenatal endophenotypic susceptibility marker and increase the impact of both positive and negative coparenting on infant regulatory capacity. This study analyzed the moderator role of FHRV in the association between positive and negative coparenting and infant regulatory capacity at 3 months. The sample comprised 86 first-born infants and their mothers and fathers recruited at a public Health Service in Northern Portugal. FHRV was recorded during routine cardiotocography examination at the third trimester of gestation. Mothers and fathers reported on coparenting and infant regulatory capacity at 2 weeks and 3 months postpartum. FHRV moderated the association between mother's and father's negative coparenting at 2 weeks postpartum and infant regulatory capacity at three months. Infants with low FHRV presented higher regulatory capacity when mothers or fathers reported less negative coparenting, while lower regulatory capacity when mothers or fathers reported more negative coparenting, than infants with high FHRV. Findings suggested lower FHRV as a prenatal endophenotypic susceptibility marker that increases the impact of negative coparenting on infant regulatory capacity.

La más baja variabilidad del pulso cardíaco fetal (FHRV) pudiera ser un marcador determinante de la susceptibilidad endofenotípica prenatal y aumentar el impacto de la crianza compartida tanto positiva como negativa sobre la capacidad regulatoria del infante. Este estudio analizó el papel moderador de FHRV en la asociación entre la positiva y negativa crianza compartida y la capacidad regulatoria del infante a los tres meses. El grupo muestra estaba compuesto de 86 infantes primerizos y sus mamás y papás. Se grabó la FHRV durante una examinación de cardiotocografía de rutina en el tercer trimestre de la gestación. Las mamás y los papás reportaron acerca de la crianza compartida y la capacidad regulatoria del infante a las dos semanas y a los tres meses después del parto. La FHRV moderó la asociación entre la crianza compartida negativa de la mamá y del papá a las dos semanas después del parto y la capacidad regulatoria del infante a los tres meses. Los infantes con baja FHRV presentaron una capacidad regulatoria más alta cuando las mamás o los papás reportaron una crianza compartida menos negativa, mientras que la capacidad regulatoria más baja se dio cuando las mamás o los papás reportaron una crianza compartida más negativa, que los infantes con una FHRV alta. Los resultados señalan la más baja FHRV como un marcador determinante de la susceptibilidad endofenotípica prenatal que aumenta el impacto de la crianza compartida negativa sobre la capacidad regulatoria del infante. Los infantes con baja FHRV pueden ser aquellos que mejor desarrollan mecanismos de autorregulación en la presencia de una crianza compartida menos negativa, mientras que están bajo alto riesgo de problemas regulatorios en la presencia de una crianza compartida más negativa.

Une variabilité de la fréquence cardiaque fœtale (VFCF) plus basse pourrait être un marqueur de sensibilité endophénotypique prénatale et augmenter l'impact du coparentage positif et négatif sur la capacité régulatoire du nourrisson. Cette étude a analysé le rôle modérateur de la VFCF dans le lien entre le coparentage positif et négatif et la capacité régulatoire du nourrisson à trois mois. Cet échantillon a inlu 86 nourrisson premiers nés et leurs mères et pères. La VFCF a été enregistrée penfdant un examen de cardiotocographie de routine au troisième trimestre de la grossesse. Les mères et les pères ont fait état de leur coparentage et de la capacité régulatoire du nourrisson à deux semaines et à trois mois postpartum. La VFCF a modéré le lien entre le coparentage négatif de la mère et du père à deux mois postpartum et la capacité régulatoire du nourrisson à trois mois. Les nourrissons avec une VFCF basse ont présenté une capacité régulatoire plus élevée lorsque les mères ou les pères ont signalé moins de coparentage négatif, alors qu'ils ont présenté une capacité régulatoire plus basse lorsque les mères ou les pères ont signalé un coparentage plus négatif, que les nourrissons avec une VFCF élevée. Les résultats ont suggéré une VFCF plus basse comme un marqueur de sensibilité endophénotypique prénatale qui augmente l'impact de coparentage négatif sur la capacité régulatoire du nourrisson. Les enfants avec une VFCF basse peuvent être ceux qui développent mieux leurs mécanismes auto-régulatoires en présence de moins de coparentage négatif, tout en étant à haut risque de problèmes régulatoires en présence de plus de coparentage négatif.

Inactivation of MST1/2 Controls Macrophage Polarization to Affect Macrophage-Related Disease via YAP and Non-YAP Mechanisms.

Macrophage polarization is a critical process that regulates in inflammation, pathogen defense, and tissue repair. Here we demonstrate that MST1/2, a core kinase of Hippo pathway and a recently identified regulator of inflammation, plays a significant role in promoting M2 polarization. We provide evidence that inhibition of MST1/2, achieved through either gene-knockout or pharmacological treatment, leads to increased M1 polarization in a YAP-dependent manner, resulting in the development of M1-associated inflammatory disorders. Moreover, MST1/2 inhibition also leads to a substantial reduction in M2 polarization, but this occurs through the STAT6 and MEK/ERK signaling. The STAT6 is independent of YAP, but MEK/ERK is dependent of YAP. Consistent with these observations, both MST1/2-conditional knockout mice and wild-type mice treated with XMU-MP-1, a chemical inhibitor of MST1/2, exhibited reduced M2-related renal fibrosis, while simultaneously displaying enhanced LPS-mediated inflammation and improved clearance of MCR3-modified gram-negative bacteria. These findings uncover a novel role of MST1/2 in regulating macrophage polarization and establish it as a potential therapeutic target for the treatment of macrophage-related fibrotic diseases.

Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury.

BACKGROUND: Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have a more rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. METHODS: UUO was induced in 10-12 weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100 mg/kg, I.P daily), UUO, and UUO plus PCA. RESULTS: After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. CONCLUSION: Our findings suggest a differential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/ß-catenin signaling pathway.

Fibroblast growth factor 21 (FGF21) is a key regulator of energy metabolism. Recent studies suggested that serum FGF21 levels increase with declining renal function. However, the link between FGF21 and kidney diseases and the direct effect of FGF21 in renal fibrosis remains unclear. In this study, FGF21 was upregulated in unilateral ureteral obstruction (UUO)-induced renal fibrosis and cellular fibrosis induced by transforming growth factor-ß, and renal expression of FGF21 was positively correlated with fibrosis markers. Additionally, FGF21 was regulated by Wnt/ß-catenin signaling pathway. The knockdown and overexpression of FGF21 in mouse tubular epithelial cells demonstrated that FGF21 alleviates renal fibrosis by inhibiting the Wnt/ß-catenin signaling pathway. To investigate the effect of FGF21 on renal fibrosis in vivo, we established an overexpression model by injecting the plasmid in mice and found that FGF21 overexpression relieved UUO-induced renal fibrosis and renal inflammatory response. Taken together, FGF21 is upregulated with the activation of Wnt/ß-catenin signaling pathway and alleviates renal fibrosis by inhibiting the activation of Wnt/ß-catenin signaling pathway in a negative feedback mode. These results provide a new understanding for the source of elevated serum FGF21 in patients with chronic kidney disease and prove that FGF21 is a direct inhibitor of the progression of renal fibrosis, thus providing novel therapeutic intervention insights for renal fibrosis.

SNHG16/miR-205/HDAC5 is involved in the progression of renal fibrosis.

Renal interstitial fibrosis (RIF) represents an irreversible and progressive pathological manifestation of chronic renal disease, which ultimately leads to end-stage renal disease. Long noncoding RNAs (lncRNAs) have been suggested to be involved in the progression of RIF. Small nucleolar RNA host gene 16 (SNHG16), a member of lncRNAs, has been found to be involved in the progression of pulmonary fibrosis. This paper first researched the effect of SNHG16 on renal fibrosis. We established a unilateral ureteral obstruction (UUO)-induced mouse RIF model by ligation of the left ureter to evaluate the biological function of SNHG16 in RIF. As a result, SNHG16 was upregulated in UUO-induced renal fibrotic tissues. Knockdown of SNHG16 inhibited RIF and reduced alpha-smooth muscle actin (α-SMA), fibronectin, and college IV expression. miR-205 was a target of SNHG16, and downregulated in UUO-induced renal fibrotic tissues. Inhibition of miR-205 promoted RIF and increased the expression of α-SMA, college IV, and fibronectin. Overexpression of SNHG16 promoted the UUO-induced RIF, but miR-205 abrogated this effect of SNHG16. Histone deacetylase 5 (HDAC5) showed high expression in UUO-induced renal fibrotic tissues. Knockdown of HDAC5 significantly reduced α-SMA, fibronectin, and college IV expression in renal tissues of UUO-induced mice. Inhibition of miR-205 promoted HDAC5 expression, but knockdown of SNHG16 inhibited HDAC5 expression in renal tissues of UUO-induced mice. In conclusion, SHNG16 is highly expressed in renal fibrotic tissues of UUO-induced mice. Knockdown of SHNG16 may prevent UUO-induced RIF by indirectly upregulating HDAC5 via targeting miR-205. SHNG16 may be novel target for treating renal fibrosis.

Role of protease-activated receptor 4 in mouse models of acute and chronic kidney injury.

Protease-activated receptor 4 (PAR4) is a G protein-coupled receptor activated by thrombin. In the platelet, response to thrombin PAR4 contributes to the predominant procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet-stimulated inflammation. In addition, PAR4 is expressed in other cell types, including endothelial cells. Under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout (KO) studies have determined a role for PAR4 in ischemia-reperfusion injury in the brain, and PAR4 KO mice display normal cardiac function but present less myocyte death and cardiac dysfunction in response to acute myocardial infarction. Although PAR4 has been reported to be expressed within the kidney, the contribution of PAR4 to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 KO mice are protected against kidney injury in two mouse models. First, PAR4 KO mice are protected against induction of markers of both fibrosis and inflammation in two different models of kidney injury: 1) 7 days following unilateral ureter obstruction (UUO) and 2) an AKI-CKD model of ischemia-reperfusion followed by 8 days of contralateral nephrectomy. We further show that PAR4 expression in the kidney is low in the control mouse kidney but induced over time following UUO. PAR4 KO mice are protected against blood urea nitrogen (BUN) and glomerular filtration rate (GFR) kidney function pathologies in the AKI-CKD model. Following the AKI-CKD model, PAR4 is expressed in the collecting duct colocalizing with Dolichos biflorus agglutinin (DBA), but not in the proximal tubule with Lotus tetragonolobus lectin (LTL). Collectively, the results reported in this study implicate PAR4 as contributing to the pathology in mouse models of acute and chronic kidney injury.NEW & NOTEWORTHY The contribution of the thrombin receptor protease-activated receptor 4 (PAR4) to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 expression is upregulated after kidney injury and PAR4 knockout (KO) mice are protected against fibrosis following kidney injury in two mouse models. First, PAR4 KO mice are protected against unilateral ureter obstruction. Second, PAR4 KO mice are protected against an AKI-CKD model of ischemia-reperfusion followed by contralateral nephrectomy.

BMAL1 inhibits renal fibrosis and renal interstitial inflammation by targeting the ERK1/2/ELK-1/Egr-1 axis.

RATIONALE: Renal fibrosis and renal interstitial inflammation due to hydronephrosis are associated with progressive chronic kidney disease (CKD). The clock gene BMAL1 is thought to be involved in various diseases, including hypertension, diabetes, etc. However, little is known about how BMAL1 regulates renal fibrosis and renal interstitial inflammation in obstructed kidneys. METHODS: The expression level of BMAL1 in UUO was examined using the GEO database. Lentivirus, siRNA and adeno-associated virus were used to modulate BMAL1 levels in HK-2 cells and mouse kidney. qRT-PCR, immunofluorescence staining, histological analysis, ELISA and Western blot were used to determine the level of fibrin deposition and the release of inflammatory factors. Immunofluorescence staining and western blotting were used to examine the interaction between BMAL1 and the ERK1/2/ELK-1/Egr-1 axis. RESULTS: Bioinformatics analysis and in vivo experiments in this study showed that the expression level of BMAL1 in UUO model kidneys was higher than that in normal kidneys. We then found that downregulation of BMAL1 promoted the production of extracellular matrix (ECM) proteins and proinflammatory factors in vivo and in vitro, whereas upregulation inhibited this process. In addition, we demonstrated that the ERK1/2/ELK-1/Egr-1 axis is an important pathway for BMAL1 to play a regulatory role, and the use of PD98059 abolished the promoting effect of down-regulation of BMAL1 on fibrosis and inflammation. CONCLUSIONS: Our findings suggest that BAML1 can target the ERK1/2/ELK-1/Egr-1 axis to suppress fibrotic progression and inflammatory events in obstructed kidneys, thereby inhibiting the development of CKD.

Looking back to light the path forward: Ghosts in the Nursery revisited.

The infant health movement was launched nearly 50 years ago with the publication of the now classic paper, Ghosts in the Nursery: A psychoanalytic approach to the problems of impaired infant-mother relationships, written by Selma Fraiberg, Edna Adelson, and Vivian Shapiro (1975). This paper offers us lessons for infant mental health practice that have been proven true time and again over the last 50 years. These lessons both underscore the factors essential to clinical progress across a range of interventions, and remind us of the significant challenges we face in these times of massive, global trauma and oppression, extreme economic hardship, and systemic racism. This commentary reviews the key lessons of Fraiberg and her colleagues' classic paper, addresses some of the challenges inherent in retaining the breadth and substance of Fraiberg's model in contemporary practice, and proposes a model for conceptualizing infant and early childhood mental health practice that is geared toward building the relational foundations of reflection (Slade, 2023).

Hace casi cincuenta años que el movimiento de salud infantil se inició con la publicación del ahora clásico ensayo Fantasmas en la guardería: Un acercamiento sicoanalítico a los problemas de relaciones infante-madre deterioradas, escrito por Selma Fraiberg, Edna Adelson y Vivian Shapiro (1975). Fantasmas en la guardería nos ofrece lecciones para la práctica de la salud mental infantil cuya validez ha sido demostrada una y otra vez a lo largo de los últimos 50 años. Estas lecciones enfatizan los factores que son esenciales para el progreso clínico a lo largo de una gama de intervenciones. Ellos también nos recuerdan los retos significativos que enfrentamos en estos tiempos de trauma y opresión global masivas, adversidades económicas extremas y racismo sistémico. Este comentario revisa las lecciones claves del clásico ensayo de Freiberg y sus colegas, se ocupa de algunos de los desafíos inherentes para mantener la amplitud y sustancia del modelo de Freiberg en la práctica contemporánea y propone un modelo para la conceptualización de la práctica de salud mental infantil y la temprana niñez, el cual está dirigido a establecer los cimientos de la reflexión con base en la relación (Slade, 2023) en la práctica clínica.

Le mouvement de la santé du nourrisson a été lancé il y a cinquante ans avec la publication d'un article désormais classique intitulé Fantômes dans la chambre d'enfants: Une approche psychanalytique des problèmes des relations enfants-mères déficientes, écrit par Selma Fraibert, Edna Adelson et Vivian Shapiro (1975). Fantômes dans la chambre d'enfants nous offre des leçons pour la pratique de santé mentale du nourrisson qui se sont avérées vraies au fil des 50 dernières années. Ces leçons soulignent les facteurs essentiels au progrès clinique au travers d'une gamme d'interventions. Elles nous rappellent également les défis importants auxquels nous faisons face à cette époque de trauma et d'oppression massive globale, de difficultés économiques extrêmes et de racisme systémique. Ce commentaire passe en revue les leçons clés de l'article classique de Fraibert et ses collègues, en adressant certains des défis inhérents à la nécessité de retenir l'ampleur et la substance du modèle de Fraiberg dans la pratique contemporaine et en proposant un modèle pour la conceptualisation de la pratique de santé mentale du nourrisson et de la petite enfance qui soit axé sur la construction de fondations relationnelles sur la réflexion (Slade 2023) dans la pratique Clinique.

The role of murine M1 macrophages from different sources in unilateral ureteral obstruction.

Introduction: The unilateral ureteral obstruction (UUO) model is the most extensively used model to investigate chronic renal fibrosis. Macrophages play a critical role in the UUO model. We aimed to analyze the phenotype of macrophages from different sources activated in vitro and explore the role of M1 macrophages from various sources in UUO. Material and methods: C57BL/6 mice were randomly allocated to five different groups (n = 5 per group): the sham-operated control group, PBS-treated (UUO + PBS) group, bone marrow-derived M1 macrophage-treated (UUO + BM1) group, peritoneal M1 macrophage-treated (UUO + PM1) group, and splenic M1 macrophage-treated (UUO + SPM1) group. After M1 macrophages were injected into the tail vein of UUO-treated mice, renal fibrosis indexes were determined using HE, Masson staining, and α-SMA. Results: Compared to those in the UUO + PBS group, the pathological changes were much more severe in the UUO + BM1, UUO + PM1, and UUO + SPM1 groups. Compared to that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1 group, the collagen area in the UUO + PM1 group was higher at post-UUO day 5 (p < 0.01). The expression of α-SMA in the UUO + PM1 group was higher than that in the UUO + PBS group, UUO + BM1 group, and UUO + SPM1group (p < 0.001). Conclusions: The M1 macrophages cultured in vitro were reinjected into mice and aggravated kidney injury and fibrosis. Compared with BM1 and SPM1, PM1 demonstrated a stronger effect on inducing renal injury and fibrosis.

Omega-3 Fatty Acids Attenuate Renal Fibrosis via AMPK-Mediated Autophagy Flux Activation.

The unilateral ureteral obstruction (UUO) injury model is well-known to mimic human chronic kidney disease, promoting the rapid onset and development of kidney injury. ω3-poly unsaturated fatty acids (PUFAs) have been observed to protect against tissue injury in many disease models. In this study, we assessed the efficacy of ω3-PUFAs in attenuating UUO injury and investigated their mechanism of action. The immortalized human proximal tubular cells human kidney-2 (HK2) were incubated for 72 h with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) in various concentrations, in the presence or absence of transforming growth factor (TGF)-ß. DHA/EPA reduced the epithelial-mesenchymal transition in the TGF-ß-treated HK2 cells by enhancing autophagy flux and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. C57BL/6 mice were divided into four groups and treated as follows: sham (no treatment, n = 5), sham + ω3-PUFAs (n = 5), UUO (n = 10), and UUO + ω3-PUFAs (n = 10). Their kidneys and blood were harvested on the seventh day following UUO injury. The kidneys of the ω3-PUFAs-treated UUO mice showed less oxidative stress, inflammation, and fibrosis compared to those of the untreated UUO mice. Greater autophagic flux, higher amounts of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and Atg7, lower amounts of p62, and higher levels of cathepsin D and ATP6E were observed in the kidneys of the omega-3-treated UUO mice compared to those of the control UUO mice. In conclusion, ω3-PUFAs enhanced autophagic activation, leading to a renoprotective response against chronic kidney injury.

3D autofluorescence imaging of hydronephrosis and renal anatomical structure using cryo-micro-optical sectioning tomography.

Rationale: Mesoscopic visualization of the main anatomical structures of the whole kidney in vivo plays an important role in the pathological diagnosis and exploration of the etiology of hydronephrosis. However, traditional imaging methods cannot achieve whole-kidney imaging with micron resolution under conditions representing in vivo perfusion. Methods: We used in vivo cryofixation (IVCF) to fix acute obstructive hydronephrosis (unilateral ureteral obstruction, UUO), chronic spontaneous hydronephrosis (db/db mice), and their control mouse kidneys for cryo-micro-optical sectioning tomography (cryo-MOST) autofluorescence imaging. We quantitatively assessed the kidney-wide pathological changes in the main anatomical structures, including hydronephrosis, renal subregions, arteries, veins, glomeruli, renal tubules, and peritubular functional capillaries. Results: By comparison with microcomputed tomography imaging, we confirmed that IVCF can maintain the status of the kidney in vivo. Cryo-MOST autofluorescence imaging can display the main renal anatomical structures with a cellular resolution without contrast agents. The hydronephrosis volume reached 26.11 ± 6.00 mm3 and 13.01 ± 3.74 mm3 in 3 days after UUO and in 15-week-old db/db mouse kidneys, respectively. The volume of the cortex and inner stripe of the outer medulla (ISOM) increased while that of the inner medulla (IM) decreased in UUO mouse kidneys. Db/db mice also showed an increase in the volume of the cortex and ISOM volume but no atrophy in the IM. The diameter of the proximal convoluted tubule and proximal straight tubule increased in both UUO and db/db mouse kidneys, indicating that proximal tubules were damaged. However, some renal tubules showed abnormal central bulge highlighting in the UUO mice, but the morphology of renal tubules was normal in the db/db mice, suggesting differences in the pathology and severity of hydronephrosis between the two models. UUO mouse kidneys also showed vascular damage, including segmental artery and vein atrophy and arcuate vein dilation, and the density of peritubular functional capillaries in the cortex and IM was reduced by 37.2% and 49.5%, respectively, suggesting renal hypoxia. In contrast, db/db mouse kidneys showed a normal vascular morphology and peritubular functional capillary density. Finally, we found that the db/db mice displayed vesicoureteral reflux and bladder overactivity, which may be the cause of hydronephrosis formation. Conclusions: We observed and compared main renal structural changes in hydronephrosis under conditions representing in vivo perfusion in UUO, db/db, and control mice through cryo-MOST autofluorescence imaging. The results indicate that cryo-MOST with IVCF can serve as a simple and powerful tool to quantitatively evaluate the in vivo pathological changes in three dimensions, especially the distribution of body fluids in the whole kidney. This method is potentially applicable to the three-dimensional visualization of other tissues, organs, and even the whole body, which may provide new insights into pathological changes in diseases.

Role of Cannabinoid Type 2 Receptor Activation in Renal Fibrosis Induced by Unilateral Ureteric Obstruction in Rats.

Background: Chronic kidney disease (CKD) ends mostly with renal fibrosis. The effect of CB2 receptor on renal fibrosis has been unclear. The aim of this study was to investigate the effect of CB2 receptor on renal fibrosis and the mechanisms behind it. Methods: 50 adult male Sprague-Dawley rats were divided into 5 groups; normal, sham; rats had their ureters only manipulated, UUO; rats had their left ureters ligated, and JWH post; rats had their left ureters ligated and they received JWH 133 for 14 days, JWH pre+post; rats received JWH 133 for 14 days before and after UUO procedure. Serum creatinine and BUN were assessed together with tissue MDA, GSH, and catalase. Histopathological evaluation of the renal tissue by H&E and Masson's trichrome was done. Immunohistochemical staining for TGF-ß1, AQP1, Caspase-3, LC3B and p62 was performed. AQP1 and CB2 receptors genes expression was detected by quantitative RT-PCR. Results: UUO had caused severe damage in the renal tissue with reduction of the renal function parameter accompanied by increase in the collagen deposition with increase TGF-ß1 and decrease AQP1 expression. Conclusions: The improvement of these parameters with JWH-133 suggests an anti-fibrotic role of CB2 receptor activation through reduction of oxidative stress, apoptosis, and autophagy.

Enhancing early parenting in the community: Preliminary results from a learning collaborative approach to scale up Attachment and Biobehavioral Catch-up.

Attachment and Biobehavioral Catch-up (ABC) is a promising home-visiting intervention promoting sensitive caregiving and secure parent-child attachment in families with young children. The goal of this study was to examine a learning collaborative approach to disseminating ABC in a community setting. Training outcomes (e.g., trainee completion, satisfaction, effectiveness of training methods) and intervention outcomes (e.g., parent behavior, parent beliefs, child socioemotional development) were examined. Eighteen practitioners participated in the ABC learning collaborative; 13 completed training. Quantitative and qualitative measures indicated that trainees were satisfied with their experience and valued the unique collaboration opportunities offered by the learning collaborative. In addition, trainees served 67 families in the community, 37 of whom completed all sessions of ABC. The study was conducted in the United States. Racial demographics of the children in the sample included: 56.7% White, 22.4% Black/African-American, 17.9% Bi- or Multi-racial, and 3.0% unknown. Regarding ethnicity, 80.6% were Non-Hispanic/Latino, 10.4% were Hispanic/Latino, and 9.0% were unknown. Caregivers who completed ABC showed more sensitive parenting behavior and reported positive changes in their perceived self-efficacy and their beliefs around infant crying. Children who received ABC showed increased socioemotional functioning. Results demonstrate successful dissemination of ABC in the community using a learning collaborative approach.

El Alcance de Afectividad y Bio-comportamiento (ABC) es una prometedora intervención de visita a casa que promueve el cuidado sensible y una relación progenitor-niño segura en familias con niños pequeños. El propósito de este estudio fue examinar un acercamiento de aprendizaje colaborativo para diseminar el ABC en un escenario comunitario. Se examinaron los resultados de entrenamiento (v.g. que el entrenado completó el proceso, satisfacción, efectividad de los métodos de entrenamiento) y los resultados de intervención (v.g. comportamiento del progenitor, creencias del progenitor, desarrollo socioemocional del niño). Dieciocho profesionales en la práctica participaron en el proceso de aprendizaje colaborativo; 13 completaron el entrenamiento, Las medidas cuantitativas y cualitativas indicaron que quienes se entrenaban estaban satisfechos con su experiencia y valoraron las oportunidades de colaboración que el proceso de aprendizaje colaborativo ofrecía de manera única. Adicionalmente, quienes se entrenaban les sirvieron a 67 familias en la comunidad, 37 de las cuales completaron todas las sesiones del ABC. El estudio se llevó a cabo en los Estados Unidos. Los perfiles demográficos raciales de los niños incluyen: 56.7% de raza blanca, 22.4% de raza negra o Afroamericanos, 17.9% birraciales o multirraciales, con un 3.0% cuya raza se desconoce. En cuanto a la etnicidad, 80.6% no eran hispanos o latinos, 10.4% eran hispanos o latinos, con un 9.0% cuya etnicidad se desconoce. Los cuidadores que completaron el ABC mostraron una conducta de crianza más sensible y reportaron cambios positivos en cuanto a su percepción de auto efectividad y su creencia acerca del llanto del infante. Los niños que recibieron el ABC mostraron un aumento en su funcionamiento socioemocional. Los resultados demuestran una exitosa diseminación del ABC en la comunidad usando un acercamiento de aprendizaje colaborativo.

L'attachement et le rattrapage bio-comportemental (en anglais Attachment and Biobehavioral Catch-up, soit ABC) est une intervention prometteuse de visite à domicile promouvant des soins sensibles et un attachement parent-enfant sécure chez les familles avec de jeunes enfants. Le but de cette étude est d'examiner une approche collaborative d'apprentissage à la dissémination de l'ABC dans le contexte d'une communauté. Les résultats de la formation (par exemple le fait de terminer le stage, la satisfaction, l'efficacité des méthodes de formation) et les résultats de l'intervention (par exemple le comportement du parent, les croyances parentales, le développement socio-émotionnel de l'enfant) ont été examinés. Dix-huit praticiens ont participé à la collaboration d'apprentissage ABC; 13 ont terminé la formation. Les mesures quantitatives and qualitatives ont indiqué que les stagiaires étaient satisfaits de leur expérience et avaient apprécié la chance d'une collaboration unique offerte par la collaboration d'apprentissage. De plus les stagiaires ont aidé 67 familles dans la communauté, 37 d'entre elles ayant terminé toutes les séances de l'ABC. L'étude a été faite aux Etats-Unis d'Amérique. Les données démographiques raciales des enfants dans l'échantillon ont inclus: 56,7% blancs, 22,4% noirs américains, 17,9% métisses ou multi-ethniques, et 3,0% de race inconnue. Concernant l'ethnicité, 80,6% était Non-Hispaniques/Non-Latinos, 10,4% étaient Hispaniques/Latinos et 9,0% étaient d'une ethnicité inconnue. Les personnes prenant soin des enfants qui ont complété l'ABC ont fait preuve d'un comportement de parentage plus sensible et fait état de changements positifs dans leur auto-efficacité perçue et leurs croyances concernant les pleurs des bébés. Les enfants ayant reçu l'ABC ont démontré un fonctionnement socio-émotionnel plus élevé. Les résultats démontrent une dissémination réussie de l'ABC dans une communauté en utilisant une approche collaborative d'apprentissage.