Search

Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression., (© 2024. The Author(s).)

Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell-type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell-type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model., Competing Interests: Declaration of Interests The Susztak lab is supported by Boehringer Ingelheim, Lilly, Regeneron, GSK, Merck, Bayer, and Gilead for work that is not related to the current manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Liriodendron chinense (Hemsl.) Sarg, known as the Chinese tulip tree, has a long history of cultivation and utilization in many Asia countries, especially in China to use in traditional Chinese medicine for expelling "wind and dampness", a term corresponding to rheumatic fever and rheumatoid arthritis. Interestingly, the barks of Liriodendron chinense (Hemsl.) Sarg was also found in folk to treat gout. However, further experimental studies remained to confirm its uric acid-lowering effects., Aim of the Study: The aim of the study was to evaluate the protective effect of ethanol extract of the barks of Liriodendron chinense (Hemsl.) Sarg (EELC) in a mouse model of hyperuricemic nephropathy (HN) and the involved mechanisms., Materials and Methods: EELC at a respective dose of 250 mg/kg/d or 500 mg/kg/d were orally administered to HN mice induced by a mixture of adenine (160 mg/kg/d)/potassium oxonate (2.4 g/kg/d) for 21 days. At the end of the treatment, serum uric acid, kidney functions (serum creatinine, blood urea nitrogen and urine microalbumin), 24-h urine uric acid excretion, as well as kidney pathological changes were investigated by biochemical assay, histopathological score, immunofluorescence and histochemistry, RT-qPCR, and western blotting analysis., Results and Discussion: Oral administration of EELC significantly lowered serum uric acid level at 500 mg/kg (185.75 ± 15.49 μmol/L of EELC vs. 238.28 ± 20.97 μmol/L of HN model, p < 0.01) in HN mice. EELC at 500 mg/kg also remarkably reduced the levels of serum creatinine (82.92 ± 7.86 μmol/L of EELC vs. 92.08 ± 6.13 μmol/L of HN model, p < 0.0001), blood urea nitrogen (21.50 ± 1.87 mmol/L of EELC vs. 29.40 ± 3.95 mmol/L of HN model, p < 0.001) and urine microalbumin (4.25 ± 0.40 mg/L of EELC vs. 5.95 ± 0.33 mg/L of HN model, p < 0.001) to improve renal function. It also attenuated renal fibrosis, especially the high-dose of EELC. Furthermore, EELC could inhibit the activation of NF-κB, ASK1/JNK/c-Jun, JAK2/STAT3 signaling pathways and reduce the release of pro-inflammatory cytokine TNF-α in the kidneys of HN mice. Additionally, EELC remarkably increased urine uric acid excretion of HN mice, which may be achieved by the upregulation of organic anion transporter 1 (OAT1), OAT3 and ATP-binding cassette subfamily G member 2 (ABCG2) proteins., Conclusions: EELC alleviated the progression of HN by suppressing the activation of NF-κB, ASK1/JNK/c-Jun and JAK2/STAT3 signaling pathway, reducing the infiltration of inflammatory factors and uric acid accumulation in the kidney., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Accumulating evidences indicated that hyperuricemia was an independent risk factor for kidney diseases and contributed to kidney fibrosis. Preventing and treating renal fibrosis was an optimal treatment for hyperuricemia-induced kidney diseases. In the study, pterostilbene (PTE) as a bioactive component of blueberries was confirmed to possess lowering serum uric acid and renal protective functions by the decrease of serum creatinine, BUN, urine albumin, and urine albumin-to-creatinine ratio (uACR) in a mouse model of hyperuricemic nephropathy (HN). Importantly, PTE treatment remarkably alleviated renal fibrosis of HN mice indicated by the downregulation of fibronectin, collagen I and α-SMA production. Furthermore, PTE could suppress the fibrosis-related protein expressions of TGF-β1/Smad3, Src and STAT3 in the kidneys of HN mice. In conclusion, PTE suppressed the activation of TGF-β1/Smad3, Src and STAT3 signaling pathway to alleviate renal fibrosis of HN mice, highlighting that PTE was a potential antifibrotic strategy for hyperuricemic nephropathy., (Copyright © 2018 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gut microbiota and its metabolites play pivotal roles in host physiology and pathology. Short-chain fatty acids (SCFAs), as a group of metabolites, exert positive regulatory effects on energy metabolism, hormone secretion, immune inflammation, hypertension, and cancer. The functions of SCFAs are related to their activation of transmembrane G protein-coupled receptors and their inhibition of histone acetylation. Though controversial, growing evidence suggests that SCFAs, which regulate inflammation, oxidative stress, and fibrosis, have been involved in kidney disease through the activation of the gut-kidney axis; however, the molecular relationship among gut microbiota-derived metabolites, signaling pathways, and kidney disease remains to be elucidated. This review will provide an overview of the physiology and functions of SCFAs in kidney disease., Competing Interests: Disclosure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest in this work.

The macrophage-to-myofibroblast transition (MMT) process is an important pathway that contributing to renal interstitial fibrosis (RIF). Fatty acid–binding protein 4 (FABP4) deteriorated RIF via promoting inflammation in obstructive nephropathy. However, the clinical significance of FABP4 in fibrotic kidney disease remains to be determined and little is known of the FABP4 signaling in MMT. Biopsy specimens of chronic kidney disease patients and kidneys subjected to unilateral ureteral obstruction (UUO) of FABP4-deficient mice or FABP4 inhibitor-treated mice were collected for the investigation of FABP4 mediating MMT of RIF. We conducted kidney RNA-seq transcriptomes and TGF-β1-induced bone marrow–derived macrophage (BMDM) assays to determine the mechanisms of FABP4. We found that FABP4 expression correlated with RIF in biopsy specimens and the injured kidneys of UUO mice where FABP4 was co-expressed with MMT cells. In UUO mice, FABP4 deficiency and a highly selective FABP4 inhibitor BMS309403 treatment both suppressed RIF. FABP4 ablation also attenuated the UUO-induced number of MMT cells and serum amyloid A1 (Saa1) expression. The siRNA-mediated Saa1 knockdown decreased the number of MMT cells in vitro. In conclusion, FABP4 is an important factor contributing to RIF by mediating MMT, and genetic/pharmacological inhibition of FABP4 provides a novel approach for the treatment of kidney fibrosis. [ABSTRACT FROM AUTHOR]

Aims: Type 2 diabetes mellitus (T2DM) has a rising prevalence and gut microbiota involvement is increasingly recognized. Diabetic nephropathy (DN) is a major complication of T2DM. The aim of the study was to understand the gut–kidney axis by an analysis of gut microbiota composition among biopsy-proven DN, T2DM without kidney disease, and healthy control. Methods: Fecal samples were collected from 14 DNs, 14 age/gender-matched T2DMs without renal diseases (DM), 14 age and gender-matched healthy controls (HC) and household contacts (HH) of DM group. The microbiota composition was analyzed by 16sRNA microbial profiling approach. Results: Substantial differences were found in the richness of gut microbiota and the variation of bacteria population in DM compared to HC, and DN compared to DM, respectively. DM could be accurately distinguished from age/gender-matched healthy controls by the variable of genus g_Prevotella_9 (AUC = 0.9), and DN patients could be accurately distinguished from age/gender-matched DM by the variables of two genera (g_Escherichia-Shigella and g_Prevotella_9, AUC = 0.86). The microbiota composition of HH group was close to that of HC group, and was different from DM group. Under the same diet, DM could be more accurately detected by the same genus (g_Prevotella_9, AUC = 0.92). Conclusion: Gut microbiota composition was explored to be related to the occurrence of biopsy-proven DN from DM. DM could be distinguished from HC by detecting g_Prevotella_9 level in feces, while DN was different from DM by the variables of g_Escherichia-Shigella and g_Prevotella_9, which potentially contributed to the physiopathological diagnosis of DN from DM. [ABSTRACT FROM AUTHOR]

Short-chain fatty acids (SFCAs) exhibit diverse functions from kidneys to human health and diseases, and also could exert their roles in post-translational modifications (PTMs). Nowadays, novel short-chain lysine acylations derived from SFCAs have attracted more attentions, including propionylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, malonylation, succinylation, crotonylation, glutarylation, lactylation, etc. These acylations have multiple physiological effects on many diseases, which also contribute to kidney pathophysiology. Here, we summarize the role of the currently novel PTMs in the kidneys for human health and diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Rhabdomyolysis-associated acute kidney injury (AKI) is life-threatening but effective treatments is lacking. Recently, fatty acid-binding protein 4 (FABP4) has been identified as a mediator of ischemic and toxic AKI through regulating endoplasmic reticulum (ER) stress in our previous studies. However, the role of FABP4 in rhabdomyolysis-induced AKI and extended organelle dysfunctions need to be explored and validated. We firstly performed mRNA-seq and bioinformatic analysis to investigate the role of FABP4. The mouse model was established via injecting glycerol to FABP4 wild type (WT) and knockout (KO) mice. Blood biochemical, inflammatory and apoptotic parameters were measured and compared across groups. Representative pathways of ER stress and mitochondrial dysfunction were also detected and quantified. Comparing FABP4 WT and FABP4 KO model groups, FABP4 deficiency significantly attenuated renal dysfunction, by reducing serum creatinine (165.90 ± 15.61 μmol/L vs 35.5 ± 8.33 μmol/L, p < 0.0001) and blood urea nitrogen (89.78 ± 6.82 mmol/L vs 19.75 ± 5.97 mmol/L, p < 0.0001), and alleviating tubular injury scores. Inflammatory and apoptotic responses were alleviated by FABP4 genetic inhibition. Mechanistically, glycerol injection triggered ER stress characterized by activated IRE1, PERK, and ATF6 signaling pathways, and induced mitochondrial dysfunction supported by ultrastructural damage, energy metabolic derangement, and excessive mitochondrial fission (upregulated DRP1/downregulated OPA1). These two organelle dysfunctions were effectively relieved by FABP4 deficiency. Taken together, genetic inhibition of FABP4 protected against rhabdomyolysis-induced AKI via reducing ER stress as well as mitochondrial dysfunction. FABP4 might act as a novel therapeutic target in rhabdomyolysis-induced AKI. [ABSTRACT FROM AUTHOR]