Small Heat Shock Protein Beta-1 (HSPB1) Is Upregulated and Regulates Autophagy and Apoptosis of Renal Tubular Cells in Acute Kidney Injury

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

Download Full-text

Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid

Hypertension ◽

10.1161/hyp.70.suppl_1.p544 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Tomoaki Nagao ◽

Takafumi Okura ◽

Akiko Tanino ◽

Ken-ichi Miyoshi ◽

Masayoshi Kukida ◽

...

Keyword(s):

Acute Kidney Injury ◽

Folic Acid ◽

Kidney Injury ◽

Immunohistochemical Analysis ◽

Tubular Injury ◽

Histological Changes ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear. The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI). AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice. These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.

Download Full-text

Rhabdomyolysis-Induced AKI Was Ameliorated in NLRP3 KO Mice via Alleviation of Mitochondrial Lipid Peroxidation in Renal Tubular Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21228564 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8564

Author(s):

Seok Jong Song ◽

Su-mi Kim ◽

Sang-ho Lee ◽

Ju-Young Moon ◽

Hyeon Seok Hwang ◽

...

Keyword(s):

Lipid Peroxidation ◽

Acute Kidney Injury ◽

Cell Viability ◽

Kidney Injury ◽

Critical Factor ◽

Tubular Injury ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Glycerol Injection ◽

Renal Tubular

Introduction: A recent study showed that early renal tubular injury is ameliorated in Nod-like receptor pyrin domain-containing protein 3 (NLRP3) KO mice with rhabdomyolysis-induced acute kidney injury (RIAKI). However, the precise mechanism has not been determined. Therefore, we investigated the role of NLRP3 in renal tubular cells in RIAKI. Methods: Glycerol-mediated RIAKI was induced in NLRP3 KO and wild-type (WT) mice. The mice were euthanized 24 h after glycerol injection, and both kidneys and plasma were collected. HKC-8 cells were treated with ferrous myoglobin to mimic a rhabdomyolytic environment. Results: Glycerol injection led to increase serum creatinine, aspartate aminotransferase (AST), and renal kidney injury molecule-1 (KIM-1) level; renal tubular necrosis; and apoptosis. Renal injury was attenuated in NLRP3 KO mice, while muscle damage and renal neutrophil recruitment did not differ between NLRP3 KO mice and WT mice. Following glycerin injection, increases in cleaved caspase-3, poly (ADP-ribose) polymerase (PARP), and a decrease in the glutathione peroxidase 4 (GPX-4) level were observed in the kidneys of mice with RIAKI, and these changes were alleviated in the kidneys of NLRP3 KO mice. NLRP3 was upregulated, and cell viability was suppressed in HKC-8 cells treated with ferrous myoglobin. Myoglobin-induced apoptosis and lipid peroxidation were significantly decreased in siNLRP3-treated HKC-8 cells compared to ferrous myoglobin-treated HKC-8 cells. Myoglobin reduced the mitochondrial membrane potential and increased mitochondrial fission and reactive oxygen species (ROS) and lipid peroxidation levels, which were restored to normal levels in NLRP3-depleted HKC-8 cells. Conclusions: NLRP3 depletion ameliorated renal tubular injury in a murine glycerol-induced acute kidney injury (AKI) model. A lack of NLRP3 improved tubular cell viability via attenuation of myoglobin-induced mitochondrial injury and lipid peroxidation, which might be the critical factor in protecting the kidney.

Download Full-text

Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury

Renal Failure ◽

10.3109/0886022x.2016.1160724 ◽

2016 ◽

Vol 38 (5) ◽

pp. 831-837 ◽

Cited By ~ 35

Author(s):

Yan Xu ◽

Min Guo ◽

Wei Jiang ◽

Hui Dong ◽

Yafei Han ◽

...

Keyword(s):

Acute Kidney Injury ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Kidney Injury ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Ischemic Acute Kidney Injury ◽

Renal Tubular

Download Full-text

Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00546.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. F502-F515 ◽

Cited By ~ 31

Author(s):

Yingfeng Shi ◽

Liuqing Xu ◽

Jinhua Tang ◽

Lu Fang ◽

Shuchen Ma ◽

...

Keyword(s):

Acute Kidney Injury ◽

Therapeutic Potential ◽

Apoptotic Cell ◽

Kidney Injury ◽

Acute Injury ◽

Tubular Damage ◽

Renal Tubules ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.

Download Full-text

RacGAP1 ameliorates acute kidney injury by promoting proliferation and suppressing apoptosis of renal tubular cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2020.04.140 ◽

2020 ◽

Vol 527 (3) ◽

pp. 624-630

Author(s):

Weiran Zhou ◽

Shuan Zhao ◽

Sujuan Xu ◽

Zhaoxing Sun ◽

Yiran Liang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Download Full-text

EGFR activity is required for renal tubular cell dedifferentiation and proliferation in a murine model of folic acid-induced acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00553.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. F356-F366 ◽

Cited By ~ 39

Author(s):

Song He ◽

Na Liu ◽

George Bayliss ◽

Shougang Zhuang

Keyword(s):

Acute Kidney Injury ◽

Folic Acid ◽

Kidney Injury ◽

Tubular Cell ◽

Renal Tubular Cell ◽

Wild Type ◽

Cell Dedifferentiation ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Proliferation of dedifferentiated intrinsic renal tubular cells has been recognized to be the major cellular event that contributes to renal repair after acute kidney injury (AKI). However, the underlying mechanism that initiates renal tubular dedifferentiation in vivo remains unexplored. Here we investigated whether epidermal growth factor receptor (EGFR) mediates this process in a murine model of folic acid (FA)-induced AKI using waved-2 mice that have reduced tyrosine kinase activity of EGFR and gefitinib, a specific EGFR inhibitor. Administration of FA for 48 h induced EGFR phosphorylation in the kidney of wild-type mice, but this was inhibited in waved-2 mice and wild-type mice given gefitinib. Compared with wild-type mice, waved-2 mice and wild-type mice treated with gefitinib had increased renal dysfunction, histologic damage, and tubular cell apoptosis after FA administration. PAX2, a dedifferentiation marker, and proliferating cell nuclear antigen, a proliferating marker, were highly expressed in renal tubular cells in wild-type mice; however, their expression was largely inhibited in the kidney of waved-2 mice. Inhibition of EGFR with gefitinib also blocked FA-induced expression of these two proteins in wild-type mice. Moreover, FA exposure resulted in phosphorylation of AKT, a downstream signaling molecule of the phosphatidylinositol 3-kinases pathway associated with renal epithelial proliferation in wild-type mice, and its phosphorylation was totally suppressed in waved-2 mice and wild-type mice given gefitinib. Taken together, these results suggest that EGFR activation is essential for initiation of renal tubular cell dedifferentiation and proliferation after AKI.

Download Full-text