Kidney fibrosis marks a critical phase in chronic kidney disease with its molecular intricacies yet to be fully understood. This study's deep dive into single-cell sequencing data of renal tissue during fibrosis pinpoints the pivotal role of fibroblasts and myofibroblasts in the fibrotic transformation. Through identifying distinct cell populations and conducting transcriptomic analysis, Spp1 emerged as a key gene associated with renal fibrosis. The study's experimental findings further confirm Spp1's vital function in promoting fibroblast to myofibroblast differentiation via the TGF-β/Smad signaling pathway, underscoring its contribution to fibrosis progression. The suppression of Spp1 expression notably hindered this differentiation process, spotlighting Spp1 as a promising therapeutic target for halting renal fibrosis. This condensed summary encapsulates the essence and findings of the original research within the specified word limit.

This study investigated rumen fermentation and histological and microbial diversity in male Hu lamb fed diets with different metabolizable energy (ME) levels (MEA, 9.17 MJ/kg, MEB, 10.00 MJ/kg, and MEC, 10.82 MJ/kg). Thirty-six male Hu lambs were randomly allotted to three treatments, and the feeding trial lasted for 67 days. Rumen fermentation results suggest that the iso-valerate had a significant effect on dietary energy level. The papillary height (PH) of rumen was the highest in the MEB group, the crypt depth (CD) was significantly increased in the duodenum and jejunum, and the villus height (VH)-to-CD ratio (VH/CD) was significantly decreased in the duodenum by increasing dietary energy levels; the VH, villus width (VW), and VH/CD also had significant differences in the ileum. 16S rRNA sequencing results showed that the operational taxonomic units (OTUs) number, the ACE, and Chao1 indices were linearly decreased by increasing dietary energy level; 24 phyla including 124 genera were identified, and the relative abundance of Papillibacter and Quinella linearly decreased by increasing the dietary energy level. Compared to MEA and MEB groups, the relative abundance of unidentified_Veillonellaceae and Anaerovibrio was significantly increased in the MEC group at the genus level. The relative abundance of the carbohydrate metabolism pathway predicted by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was linearly increased by increasing the dietary energy levels. Three metabolic pathways identified in Kyoto Encyclopedia of Genes and Genomes (KEGG) level 3 were significantly influenced as the dietary energy level increased. In summary, these results demonstrated that the dietary energy levels affected the rumen fermentation parameters, morphological structures of the gastrointestinal tract (GIT), and the composition and function of rumen microflora in male Hu sheep.

Nonalcoholic fatty liver disease is the most common liver disease worldwide. Hepatic steatosis and oxidative stress are the main characteristics of NAFLD (nonalcoholic fatty liver disease), which also affect its prognosis. Bixin acts as novel Nrf2 (NF‐E2 p45‐related factor 2) activator with the cytoprotection against oxidative stress and inflammation; this study mainly focused on the mechanism of Nrf2 activation by bixin and explored its potential feasibilities in long‐term high‐fat diet‐ (HFD‐) caused hepatic steatosis and inflammatory response in vitro and in vivo. Bixin was found to activate Nrf2 signals by the modification of critical Keap1 (Kelch‐like ECH‐associated protein 1) cystine and competitive interaction with Keap1 with upregulating P62 mRNA and protein expression. In human liver cells exposed to FFA (free fatty acid), bixin displayed a pronounced cytoprotective activity with upregulation of Nrf2‐mediated gene expression, such as PPARα and its targets related with fatty acid oxidation. In HFD‐fed mice, systemic administration of bixin attenuated lipid accumulation, decreased oxidant inflammatory damage in the liver, and reduced circulating lipid levels through Nrf2. Different from most of other established inducers, bixin activated Nrf2 signals through two different mechanisms with safe administration for protection of oxidant inflammatory damage and attenuation of lipid accumulation in the in vivo long‐term HFD‐fed mice. Bixin represents a prototype Nrf2 activator that displays cytoprotective activity upon system administration targeting hepatic steatosis and oxidant inflammation originating from long‐term HFD‐fed mice. And bixin‐based Nrf2‐directed systemic intervention may also provide therapeutic benefit in protecting other organs in the process of metabolic syndrome.

Key Points: We mapped dynamic extracellular matrix remodeling in AKI and identified microfibrillar-associated protein 2 (Mfap2) as a key repair mediator. Mfap2 drove mechanometabolic signaling through a large tumor suppressor kinase 1–mediated noncanonical Hippo pathway. The Mfap2-estrogen receptor 2-3-hydroxy-3-methylglutaryl-CoA synthase 2 circuit may be a druggable node for mitigating AKI. Background: Although traditionally considered a tubule-centric disorder, AKI is increasingly recognized as involving early and active participation of fibroblasts and pericytes, the primary producer of extracellular matrix (ECM). These cells are rapidly mobilized to injury sites to support repair. Therefore, successful recovery from AKI requires not only cellular regeneration but also a finely tuned ECM, which ensures structural support and transmits essential mechanical cues. Despite its importance, the mechanistic basis by which the ECM regulates AKI repair remains incompletely understood. Methods: We combined genetic and pharmacologic AKI animal models with tissue engineering approaches, data-independent acquisition–based global and phosphoproteomics, and spatial transcriptomics to profile the ECM proteome landscape of decellularized kidney matrix scaffolds after injury, uncover mechanometabolic pathways driving repair, and evaluate potential therapeutic strategies. Results: We generated a comprehensive proteomic map of the AKI kidney matrix scaffold and highlighted microfibrillar-associated protein 2 (Mfap2) as a key core matrisome component primarily derived from fibroblasts and pericytes. Mfap2 loss disrupted kidney architecture and metabolic homeostasis, aggravating AKI severity. Global proteomics revealed that Mfap2 deficiency downregulated tubular 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) through estrogen receptor 2 (Esr2)–mediated transcriptional repression and increased protein succinylation. Phosphoproteomic and spatial transcriptomic analysis showed that Mfap2 loss altered mechanotransduction, leading to mitogen-activated protein kinases hyperactivation and upregulation of large tumor suppressor kinase 1 in tubular cells, without affecting integrin receptor activity. Although large tumor suppressor kinase 1 is a key Hippo pathway kinase, its activation suppressed Esr2 transcription independently of the canonical yes-associated protein/transcriptional coactivator with PDZ-binding motif effectors and without affecting Esr2 degradation. Therapeutically, Esr2 agonist restored Hmgcs2 levels and improved kidney function in Mfap2 -deficient models. Conclusions: Mfap2, a fibroblast/pericyte-derived core matrisome component, preserved kidney architecture and supported tubular ketogenesis by regulating Hmgcs2 via Esr2 in the AKI microenvironment.

Purpose: A major limitation of long-term peritoneal dialysis (PD) is peritoneal membrane dysfunction characterized by faster peritoneal solute-transport rate (PSTR). This study aimed to identify efficient complement factors in peritoneal effluents of continuous ambulatory peritoneal dialysis (CAPD) patients that can predict the PSTR. Methods: A multiplex suspension protein array was used to screened related complement pathways in overnight peritoneal effluents among 58 CAPD patients. Then the related complement factors in lectin and classical pathways in effluents were analyzed using ELISA kits among another cohort of 129 CAPD patients. Logistic regression modeling was fitted to predict the PSTR of PD patients. Results: The multiplex suspension protein array showed complement factors including C2, C4b, C5, C5a, Factor D, Factor I, and MBL were detected in effluents of CAPD patients, and the effluent C2 Appearance rate (Ar) and C4b Ar levels were significantly correlated with D/P Cr and D/D0 glucose. The levels of effluents MASP-1 Ar, M-Ficolin Ar, C2 Ar and C4b Ar, which belong to the lectin pathway were also positively correlated with D/P Cr according the ELISA results and these parameters were expressed higher in the high and high-average (H/HA) groups according to the PET results. Moreover, effluent Masp-1 was independently associated with increased PSTR and adverse events related peritoneal transport function failure. Conclusion: This study suggested that the lectin pathway may be involved in local complement activation and peritoneal injury of PD patients, intraperitoneal level of Masp-1 was an independent predictor of increased PSTR in PD patients.