PMID- 38246328
OWN - NLM
STAT- MEDLINE
DCOM- 20240226
LR  - 20240229
IS  - 1096-0384 (Electronic)
IS  - 0003-9861 (Linking)
VI  - 753
DP  - 2024 Mar
TI  - Lrg1 silencing attenuates ischemia-reperfusion renal injury by regulating 
      autophagy and apoptosis through the TGFbeta1- Smad1/5 signaling pathway.
PG  - 109892
LID - S0003-9861(24)00011-0 [pii]
LID - 10.1016/j.abb.2024.109892 [doi]
AB  - BACKGROUND: Dysfunction in the processes of autophagy and apoptosis within renal 
      tubular epithelial cells (RTEc) contributes to renal ischemia-reperfusion injury 
      (IRI). However, the factors influencing this dysfunction remain unclear. 
      Leucine-rich alpha-2-glycoprotein 1 (Lrg1) plays a role in the progression of 
      diabetic nephropathy and kidney fibrosis by modulating the activin receptor-like 
      kinase 1 (ALK1)-Smad1/5/8 and TGF-beta1/Smad3 pathways, respectively. Therefore, we 
      aimed to investigate whether Lrg1 is involved in the pathological mechanisms of 
      renal IRI and whether its effects are related to the dysregulation of autophagy 
      and apoptosis in RTEc. METHODS: We conducted in vitro and in vivo experiments 
      using CoCl(2)-induced hypoxic human kidney-2 (HK-2) cells and mice with renal 
      IRI, respectively. Lrg1 was silenced using siRNA and lentiviral vectors in 
      HK-2 cells and mouse kidneys. Rapamycin (Rapa) and methyladenine were applied to 
      regulate autophagy in renal IRI models. RESULTS: Increased Lrg1 expression was 
      observed in hypoxic HK-2 cells and in the kidneys of mice with renal IRI. 
      Silencing of Lrg1 through siRNA and lentiviral approaches restored autophagy and 
      suppressed apoptosis in CoCl(2)-induced hypoxic HK-2 cells and renal IRI models. 
      Additionally, reduced Lrg1 expression alleviated kidney damage caused by renal 
      IRI. The downregulation of Lrg1 expression restrained the TGFbeta-Smad1/5 signaling 
      pathway in hypoxic-induced HK-2 cells and renal IRI by reducing ALK1 expression. 
      Lastly, the enhancement of autophagy, achieved through Rapa treatment, provided 
      protection against renal IRI in mice. CONCLUSIONS: Our findings suggest that Lrg1 
      silencing can be applied as a potential therapeutic target to inhibit the 
      TGFbeta1-Smad1/5 pathway, thereby enhancing autophagy and decreasing apoptosis in 
      patients with acute kidney injury.
CI  - Copyright (c) 2024 Elsevier Inc. All rights reserved.
FAU - Chen, Jianhui
AU  - Chen J
AD  - Department of Nephrology, The Third Affiliated Hospital, Southern Medical 
      University, Guangzhou, 510630, China.
FAU - Zhang, Zuoman
AU  - Zhang Z
AD  - Department of Neonatology, Nanfang Hospital, Southern Medical University, 
      Guangzhou, 510515, China.
FAU - Feng, Ling
AU  - Feng L
AD  - Department of Nephrology, Shenzhen Hospital, Southern Medical University, 
      Shenzhen, China.
FAU - Liu, Weihua
AU  - Liu W
AD  - Department of Nephrology, The Third Affiliated Hospital, Southern Medical 
      University, Guangzhou, 510630, China.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Nephrology, The Third Affiliated Hospital, Southern Medical 
      University, Guangzhou, 510630, China.
FAU - Chen, Haishan
AU  - Chen H
AD  - Department of Nephrology, The Third Affiliated Hospital, Southern Medical 
      University, Guangzhou, 510630, China.
FAU - Zou, Hequn
AU  - Zou H
AD  - Department of Nephrology, The Third Affiliated Hospital, Southern Medical 
      University, Guangzhou, 510630, China; School of Medicine, The Chinese University 
      of Hong Kong, Shenzhen, China. Electronic address: hequnzou@szu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20240119
PL  - United States
TA  - Arch Biochem Biophys
JT  - Archives of biochemistry and biophysics
JID - 0372430
RN  - 3G0H8C9362 (Cobalt)
RN  - EVS87XF13W (cobaltous chloride)
RN  - 0 (Glycoproteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Smad1 Protein)
RN  - 0 (Smad1 protein, mouse)
RN  - 0 (LRG1 protein, mouse)
RN  - 0 (LRG1 protein, human)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Tgfb1 protein, mouse)
RN  - 0 (SMAD1 protein, human)
RN  - 0 (Smad5 protein, mouse)
RN  - 0 (SMAD5 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - *Acute Kidney Injury/pathology
MH  - Apoptosis/genetics
MH  - Autophagy/physiology
MH  - *Cobalt
MH  - Glycoproteins/genetics/metabolism
MH  - Ischemia/metabolism/pathology
MH  - Kidney/pathology
MH  - Reperfusion
MH  - *Reperfusion Injury/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Signal Transduction
MH  - Smad1 Protein/metabolism
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - Ischemia-reperfusion injury
OT  - Lrg1
OT  - Renal tubular epithelial cell
OT  - TGFbeta-Smad1/5
COIS- Declaration of competing interest The authors claim that the study was conducted 
      without any potential conflicts of interest in business or financial 
      relationships.
EDAT- 2024/01/22 00:42
MHDA- 2024/02/26 06:44
CRDT- 2024/01/21 19:15
PHST- 2023/06/10 00:00 [received]
PHST- 2023/12/27 00:00 [revised]
PHST- 2024/01/11 00:00 [accepted]
PHST- 2024/02/26 06:44 [medline]
PHST- 2024/01/22 00:42 [pubmed]
PHST- 2024/01/21 19:15 [entrez]
AID - S0003-9861(24)00011-0 [pii]
AID - 10.1016/j.abb.2024.109892 [doi]
PST - ppublish
SO  - Arch Biochem Biophys. 2024 Mar;753:109892. doi: 10.1016/j.abb.2024.109892. Epub 
      2024 Jan 19.