更新于：2024-11-01

TGF-β1 x α-Klotho

更新于：2024-11-01

基本信息

关联

项与 TGF-β1 x α-Klotho 相关的药物

RJB-02

靶点

TGF-β1 x α-Klotho

作用机制

TGF-β1调节剂 [+1]

在研机构

Rejuvenate Bio, Inc.初创企业

原研机构

Rejuvenate Bio, Inc.初创企业

在研适应症

关节疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TGF-β1 x α-Klotho 相关的临床结果

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100 项与 TGF-β1 x α-Klotho 相关的转化医学

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0 项与 TGF-β1 x α-Klotho 相关的专利（医药）

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项与 TGF-β1 x α-Klotho 相关的文献（医药）

2024-09-01·Journal of Cellular Physiology

Loss of NLRP6 increases the severity of kidney fibrosis

Article

作者: Ortiz, Alberto ; Sanz, Ana B. ; Pintor‐Chocano, Aranzazu ; Sanchez‐Niño, Maria D. ; Valiño‐Rivas, Lara ; Carriazo, Sol M.

AbstractWhile NLRP3 contributes to kidney fibrosis, the function of most NOD‐like receptors (NLRs) in chronic kidney disease (CKD) remains unexplored. To identify further NLR members involved in the pathogenesis of CKD, we searched for NLR genes expressed by normal kidneys and differentially expressed in human CKD transcriptomics databases. For NLRP6, lower kidney expression correlated with decreasing glomerular filtration rate. The role and molecular mechanisms of Nlrp6 in kidney fibrosis were explored in wild‐type and Nlrp6‐deficient mice and cell cultures. Data mining of single‐cell transcriptomics databases identified proximal tubular cells as the main site of Nlrp6 expression in normal human kidneys and tubular cell Nlrp6 was lost in CKD. We confirmed kidney Nlrp6 downregulation following murine unilateral ureteral obstruction. Nlrp6‐deficient mice had higher kidney p38 MAPK activation and more severe kidney inflammation and fibrosis. Similar results were obtained in adenine‐induced kidney fibrosis. Mechanistically, profibrotic cytokines transforming growth factor beta 1 (TGF‐β1) and TWEAK decreased Nlrp6 expression in cultured tubular cells, and Nlrp6 downregulation resulted in increased TGF‐β1 and CTGF expression through p38 MAPK activation, as well as in downregulation of the antifibrotic factor Klotho, suggesting that loss of Nlrp6 promotes maladaptive tubular cell responses. The pattern of gene expression following Nlrp6 targeting in cultured proximal tubular cells was consistent with maladaptive transitions for proximal tubular cells described in single‐cell transcriptomics datasets. In conclusion, endogenous constitutive Nlrp6 dampens sterile kidney inflammation and fibrosis. Loss of Nlrp6 expression by tubular cells may contribute to CKD progression.

2024-09-01·Food and Chemical Toxicology

Polystyrene microplastics facilitate renal fibrosis through accelerating tubular epithelial cell senescence

Article

作者: Pan, Chun ; Mao, Wenwen ; Wu, Yin ; Wang, Xinglong ; Xu, Zhuobin ; Liu, Tingting ; Wang, Huihui ; Fan, Zhencheng ; Shi, Yujie ; Chen, Hao

Microplastics (MPs), emerging contaminants, are easily transported and enriched in the kidney, suggesting the kidney is susceptible to the toxicity of MPs. In this study, we explored the toxicity of MPs, including unmodified polystyrene (PS), negative-charged PS-SO₃H, and positive-charged PS-NH₂ MPs, in mice models for 28 days at a human equivalent concentration. The results showed MPs significantly increased levels of UREA, urea nitrogen (BUN), creatinine (CREA), and uric acid (UA) levels in serum and white blood cells, protein, and microalbumin in urine. In the kidney, MPs triggered persistent inflammation and renal fibrosis, which was caused by the increased senescence of tubular epithelial cells. Moreover, we identified the critical role of the Klotho/Wnt/β-catenin signaling pathway in the process of MPs induced senescence of tubular epithelial cells, promoting the epithelial-mesenchymal transformation of epithelial cells. MPs supported the secretion of TGF-β1 by senescent epithelial cells and induced the activation of renal fibroblasts. On the contrary, restoring the function of Klotho can alleviate the senescence of epithelial cells and reverse the activation of fibroblasts. Thus, our study revealed new evidence between MPs and renal fibrosis, and adds an important piece to the whole picture of the plastic pollution on people's health.

2024-08-01·Veterinary Microbiology

Gene expression in heart, kidney, and liver identifies possible mechanisms underpinning fetal resistance and susceptibility to in utero PRRSV infection

Article

作者: Lunney, J K ; Walker, K E ; Mulligan, M K ; Harding, J C S ; Jones, A ; Van Goor, A ; Pasternak, J A

Porcine reproductive and respiratory syndrome (PRRS) is one of the costliest diseases to pork producers worldwide. We tested samples from the pregnant gilt model (PGM) to better understand the fetal response to in-utero PRRS virus (PRRSV) infection. Our goal was to identify critical tissues and genes associated with fetal resilience or susceptibility. Pregnant gilts (N=22) were infected with PRRSV on day 86 of gestation. At 21 days post maternal infection, the gilts and fetuses were euthanized, and fetal tissues collected. Fetuses were characterized for PRRS viral load in fetal serum and thymus, and preservation status (viable or meconium stained: VIA or MEC). Fetuses (N=10 per group) were compared: uninfected (UNIF; <1 log/µL PRRSV RNA), resilient (HV_VIA, >5 log virus/µL but viable), and susceptible (HV_MEC, >5 log virus/µL with MEC). Gene expression in fetal heart, kidney, and liver was investigated using NanoString transcriptomics. Gene categories investigated were hypothesized to be involved in fetal response to PRRSV infection: renin- angiotensin-aldosterone, inflammatory, transporter and metabolic systems. Following PRRSV infection, CCL5 increased expression in heart and kidney, and ACE2 decreased expression in kidney, each associated with fetal PRRS susceptibility. Liver revealed the most significant differential gene expression: CXCL10 decreased and IL10 increased indicative of immune suppression. Increased liver gene expression indicated potential associations with fetal PRRS susceptibility on several systems including blood pressure regulation (AGTR1), energy metabolism (SLC16A1 and SLC16A7), tissue specific responses (KL) and growth modulation (TGFB1). Overall, analyses of non-lymphoid tissues provided clues to mechanisms of fetal compromise following maternal PRRSV infection.