IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage

IL-1 receptor (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of the podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated the podocyte IL-1R1 in mice (PKO). We then subjected PKO mice and wild-type (WT) controls to 2 glomerular injury models: nephrotoxic serum (NTS)- and adriamycin (ADR)-induced nephropathy. Surprisingly, we found IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and ADR-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between WT and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.

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AMP-Kinase mediates regulation of glomerular volume and podocyte survival

10.1101/2021.05.21.445180 ◽

2021 ◽

Author(s):

Khadija Banu ◽

Qisheng Lin ◽

John M Basgen ◽

Marina Planoutene ◽

Chengguo Wei ◽

...

Keyword(s):

Protective Role ◽

Negative Regulator ◽

Amp Kinase ◽

Glomerular Injury ◽

Podocyte Injury ◽

Kinase Activation ◽

Glomerular Volume ◽

Foot Process ◽

Injury Models

We reported that Shroom3 knockdown, via Fyn inhibition, induced albuminuria with foot process effacement (FPE) without glomerulosclerosis (FSGS) or podocytopenia. Interestingly, knockdown mice had reduced podocyte volumes. Human minimal change disease, where podocyte Fyn inactivation was reported, also showed lower glomerular volumes than FSGS. We hypothesized that lower glomerular volume prevented the progression to podocytopenia. To test this hypothesis, we utilized unilateral- and 5/6th nephrectomy models in Shroom3 knockdown mice. Knockdown mice exhibited lower glomerular volume, and less glomerular and podocyte hypertrophy after nephrectomy. FYN-knockdown podocytes had similar reductions in podocyte volume, implying Fyn was downstream of Shroom3. Using SHROOM3- or FYN-knockdown, we confirmed reduced podocyte protein content, along with significantly increased phosphorylated AMP-kinase, a negative regulator of anabolism. AMP-Kinase activation resulted from increased cytoplasmic redistribution of LKB1 in podocytes. Inhibition of AMP-Kinase abolished the reduction in glomerular volume and induced podocytopenia in mice with FPE, suggesting a protective role for AMP-Kinase activation. In agreement with this, treatment of glomerular injury models with AMP-Kinase activators restricted glomerular volume, podocytopenia and progression to FSGS. In summary, we demonstrate the important role of AMP-Kinase in glomerular volume regulation and podocyte survival. Our data suggest that AMP-Kinase activation adaptively regulates glomerular volume to prevent podocytopenia in the context of podocyte injury.

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Basic helix-loop-helix transcriptional factor MyoR regulates BMP-7 in acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00510.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. F1159-F1166 ◽

Cited By ~ 5

Author(s):

Nozomu Kamiura ◽

Junichi Hirahashi ◽

Yumi Matsuzaki ◽

Mana Idei ◽

Osamu Takase ◽

...

Keyword(s):

Kidney Injury ◽

Protective Role ◽

Wild Type ◽

Helix Loop Helix ◽

P53 Signaling ◽

Significant Difference ◽

Proximal Tubular Epithelial Cells ◽

Renal Proximal Tubular ◽

Induced Apoptosis

MyoR was originally identified as a transcriptional repressor in embryonic skeletal muscle precursors, but its function in adult kidney has not been clarified. In this study, we tried to clarify the functional role of MyoR using MyoR−/− mice. Cisplatin induced a significantly higher degree of severe renal dysfunction, tubular injury, and mortality in MyoR−/− mice than in wild-type mice. The injection of cisplatin significantly increased the number of apoptotic cells in the kidney tissues of MyoR−/− mice, compared with that in wild-type mice. To clarify the mechanism of severe cisplatin-induced damage and apoptosis in MyoR−/− mice, we focused on the p53 signaling pathway and bone morphogenic protein-7 (BMP-7). Treatment with cisplatin significantly activated p53 signaling in cultured renal proximal tubular epithelial cells (RTECs) in both wild-type and MyoR−/− mice, but no significant difference between the groups was observed. The injection of cisplatin significantly increased the expression of BMP-7 in the kidney tissues of wild-type mice, but no increase was observed in the MyoR−/− mice. Treatment with cisplatin significantly increased the expression of BMP-7 in cultured RTECs from wild-type mice but not in those from MyoR−/− mice. Moreover, treatment with recombinant BMP-7 rescued the cisplatin-induced apoptosis in RTECs from MyoR−/− mice. Taken together, our results demonstrate a new protective role of MyoR in adult kidneys that acts through the regulation of BMP-7.

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CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22147642 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7642

Author(s):

Zoran V. Popovic ◽

Felix Bestvater ◽

Damir Krunic ◽

Bernhard K. Krämer ◽

Raoul Bergner ◽

...

Keyword(s):

Kidney Disease ◽

Kidney Diseases ◽

Kidney Injury ◽

Membranous Glomerulonephritis ◽

Human Kidney ◽

Protective Role ◽

Control Group ◽

Podocyte Injury ◽

Ccr2 Expression ◽

Cd73 Expression

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.

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A review of oxidative stress in acute kidney injury: protective role of medicinal plants-derived antioxidants

African Journal of Traditional Complementary and Alternative Medicines ◽

10.4314/ajtcam.v10i4.15 ◽

2013 ◽

Vol 10 (4) ◽

Cited By ~ 1

Author(s):

S Palipoch

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Medicinal Plants ◽

Kidney Injury ◽

Protective Role

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Susceptibility to Entamoeba histolytica intestinal infection is related to reduction in natural killer T-lymphocytes in C57BL/6 mice

Infectious Disease Reports ◽

10.4081/idr.2012.e27 ◽

2012 ◽

Vol 4 (1) ◽

pp. 27 ◽

Cited By ~ 3

Author(s):

Fabrício M.S. Oliveira ◽

Bernardo C. Horta ◽

Luana O. Prata ◽

Andrezza F. Santiago ◽

Andréa C. Alves ◽

...

Keyword(s):

T Lymphocytes ◽

Natural Killer ◽

Entamoeba Histolytica ◽

Protective Role ◽

Amoebic Liver Abscess ◽

Wild Type ◽

Quantitative Analyses ◽

Cd1 Mice ◽

Natural Killer T

Entamoeba histolytica is a protozoan that causes amoebiasis. Recent studies demonstrated that natural killer T lymphocytes (NKT) are critical for preventing the development of amoebic liver abscess. In spite of that, there are only a handful of studies in the area. Herein, we explored the role of NKT cells in E. histolytica infection using C57BL/6 wild-type and CD1-/- mice. Animals were inoculated with E. histolytica and sacrificed 48 hours later to collect caecum samples that were used for quantitative analyses of lesions, trophozoites, NK1.1+ T lymphocytes and expression of the mucus protein MUC-2 by immunohistochemistry technique. Quantitative analyses confirmed that the frequency of NK1.1+ T cells was significantly lower in samples from C57BL/6 CD1-/- mice as compared to their wild type (WT) counterparts. The extension of necrotic mucosa was larger and the number of trophozoites higher in Entamoeba (Eh)-infected CD1-/- mice when compared with Eh-infected WT mice. In mice from both groups, noninfected (CTRL) and Eh-infected CD1-/-, there was a reduction in the thickness of the caecal mucosa and in the MUC-2-stained area in comparison with CTRL- and Eh-WT mice. Our results showed that NKT lymphocytes contribute to resistance against Entamoeba histolytica infection and to the control of inflammation in the colitis induced by infection. The presence of a normal epithelial layer containing appropriate levels of mucus had also a protective role against infection.

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The Protective Effect of Shen Qi Wan on Adenine-Induced Podocyte Injury

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/5803192 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Yiyou Lin ◽

Jieying Zhang ◽

Yunbo Fu ◽

Liting Ji ◽

Luning Lin ◽

...

Keyword(s):

Metabolic Disorders ◽

Kidney Injury ◽

Glomerular Filtration Barrier ◽

Podocyte Injury ◽

Nitrogen Levels ◽

Filtration Barrier ◽

Transmission Electron ◽

High Level ◽

Food Processes

Podocytes are a special type of differentiated epithelial cells that maintain the glomerular filtration barrier in the kidney. Injury or damages in podocytes can cause kidney-related disorders, like CKD. The injury or dysfunction of podocytes can occur by different metabolic disorders. Due to the severity and complexity of podocyte injuries, this state is considered as a serious health issue worldwide. Here, we examined and addressed the efficacy of an alternative Chinese medicine, Shen Qi Wan (SQW), on podocyte-related kidney injury. We evaluated the role and mechanism of action of SQW in podocyte injury. We observed that SQW significantly reduced 24-hour urinary protein and blood urea nitrogen levels and alleviated the pathological damage caused by adenine. Moreover, SQW significantly decreased the expression of nephrin and increased the expression of WT1 and AQP1 in the kidney of mice treated with adenine. We observed that SQW did not effectively reduce the high level of proteinuria in AQP1−/− mice indicating the prominent role of AQP1 in the SQW-ameliorating pathway. Transmission electron microscopy (TEM) images indicated the food processes effacement in AQP1−/− mice were not lessened by SQW. In conclusion, podocyte injury could alter the pathological nature of the kidney, and SQW administration relieves the nature of pathogenesis by activating AQP1.

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Stanniocalcin-1 Alleviates Contrast-Induced Acute Kidney Injury by Regulating Mitochondrial Quality Control via the Nrf2 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/1898213 ◽

2020 ◽

Vol 2020 ◽

pp. 1-17 ◽

Cited By ~ 3

Author(s):

Fei Zhao ◽

Li-Xin Feng ◽

Qian Liu ◽

Hong-Shen Wang ◽

Cheng-Yuan Tang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Quality Control ◽

Kidney Injury ◽

Protective Role ◽

Mitochondrial Quality Control ◽

Therapy Strategy ◽

Nrf2 Signaling Pathway ◽

Short And Long Term ◽

Renal Tubular

Contrast-induced acute kidney injury (CI-AKI) is the third common cause of acute kidney injury (AKI), which is associated with poor short- and long-term outcomes. Currently, effective therapy strategy for CI-AKI remains lacking. Stanniocalcin-1 (STC1) is a conserved glycoprotein with antiapoptosis and anti-inflammatory functions, but the role of STC1 in controlling CI-AKI is unknown. Here, we demonstrated a protective role of STC1 in contrast-induced injury in cultured renal tubular epithelial cells and CI-AKI rat models. Recombinant human STC1 (rhSTC1) regulated mitochondrial quality control, thus suppressing contrast-induced mitochondrial damage, oxidative stress, inflammatory response, and apoptotic injury. Mechanistically, activation of the Nrf2 signaling pathway contributes critically to the renoprotective effect of STC1. Together, this study demonstrates a novel role of STC1 in preventing CI-AKI and reveals Nrf2 as a molecular target of STC1. Therefore, this study provides a promising preventive target for the treatment of CI-AKI.

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Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

Scientific Reports ◽

10.1038/s41598-019-56933-7 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 2

Author(s):

Yuanbo Wu ◽

Changlong An ◽

Xiaogao Jin ◽

Zhaoyong Hu ◽

Yanlin Wang

Keyword(s):

Knockout Mice ◽

Critical Role ◽

Kidney Injury ◽

Wild Type ◽

Salt Treatment ◽

Hypertensive Nephropathy ◽

Deoxycorticosterone Acetate ◽

Kidney Fibrosis ◽

Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

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