Role of Renal Hypoxia in the Progression From Acute Kidney Injury to Chronic Kidney Disease

Ullah, Mahbub; Basile, David P.

doi:10.1016/j.semnephrol.2019.10.006

Cited by 58 publications

(43 citation statements)

References 149 publications

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“…8,[31][32][33] The loss of nephron mass and the consequent nephron hyperfiltration can lead to the activation of the renin-angiotensin system, hypertension and the subsequent glomerulosclerosis. [34][35][36] Experimental models have shown that selective epithelial injury could drive capillary sparseness, interstitial fibrosis, glomerulosclerosis and CKD, substantiating a direct role for damaged TEC in disease progression. 37 Therefore, recent research on AKI/CKD has focused on the functions of TEC.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IRE1/JNK pathway in HK‐2 cells subjected to hypoxia‐reoxygenation attenuates mesangial cells‐derived extracellular matrix production

Liang

Liu

et al. 2020

J Cellular Molecular Medi

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Endoplasmic reticulum (ER) stress and inflammatory responses play active roles in the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). Inositol‐requiring enzyme 1 (IRE1) activates c‐Jun NH2‐terminal kinase (JNK) in ER stress. Tubular epithelial cells (TEC) are the main injury target and source of AKI inflammatory mediators. TEC injury may lead to glomerulosclerosis, however, the underlying mechanism remains unclear. Here, hypoxia/reoxygenation (H/R) HK‐2 cells were used as an AKI model. To determine the partial effects of TEC injury on the glomerulus, HK‐2 cells after H/R were co‐cultured with human renal mesangial cells (HRMC). H/R up‐regulated ER stress, IRE1/JNK pathway, IL‐6 and MCP‐1 in HK‐2 cells. Stimulation of HRMC with IL‐6 enhanced their proliferation and the expression of glomerulosclerosis‐associated fibronectin and collagen IV via signal transducer and activator of transcription 3 (STAT3) activation. Similar responses were observed in HRMC co‐cultured with HK‐2 cells after H/R. IRE1/JNK inhibition reversed these injury responses in HRMC. IRE1/JNK stable knock‐down in HK‐2 cells and shRNA‐mediated STAT3 depletion in HRMC confirmed their role in inflammation/glomerulosclerosis. These findings suggest that IRE1/JNK pathway mediates inflammation in TEC, affecting mesangial cells. The inhibition of this pathway could be a feasible approach to prevent AKI‐CKD transition.

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Section: Discussionmentioning

confidence: 99%

Inhibition of IRE1/JNK pathway in HK‐2 cells subjected to hypoxia‐reoxygenation attenuates mesangial cells‐derived extracellular matrix production

Liang

Liu

et al. 2020

J Cellular Molecular Medi

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“…However, incomplete or ineffective repair may predispose to the secondary development of CKD. The AKI-to-CKD transition may result from persistent alterations in vascular, tubular, and/or interstitial compartments [ 90 ]. Our group recently proposed a central role for persistent Th17 activity in this process.…”

Section: Responses In Acute Injurymentioning

confidence: 99%

T helper 17 cells in the pathophysiology of acute and chronic kidney disease

Basile

Ullah

Collet

et al. 2021

Kidney Res Clin Pract

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As of 2017, the global burden of chronic kidney disease (CKD) was estimated to be approximately 9.1%, indicating that CKD is a significant healthcare concern worldwide. Global age-adjusted mortality rates for patients with CKD have declined in the last 30 years, and quality of life metrics decrease as glomerular filtration rate declines [1]. In the period between1990 and 2017, there was an approximate 41% increase in the number of patients with end-stage renal disease (ESRD). Despite this, CKD patients are more likely to die due to complications such as hypertension, cardiovascular disease, anemia, and bone and mineral Both acute and chronic kidney disease have a strong underlying inflammatory component. This review focuses primarily on T helper 17 (Th17) cells as mediators of inflammation and their potential to modulate acute and chronic kidney disease. We provide updated information on factors and signaling pathways that promote Th17 cell differentiation with specific reference to kidney disease. We highlight numerous clinical studies that have investigated Th17 cells in the setting of human kidney disease and provide updated summaries from various experimental animal models of kidney disease indicating an important role for Th17 cells in renal fibrosis and hypertension. We focus on the pleiotropic effects of Th17 cells in different renal cell types as potentially relevant to the pathogenesis of kidney disease. Finally, we highlight studies that present contrasting roles for Th17 cells in kidney disease progression.

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“…Renal hypoxia serves as a key player in this pathophysiology. Hypoxia is associated with HIF stabilization, which in turn profoundly damages tubular epithelial cells, activates fibroblasts, and induces inflammatory responses (16). In addition, the recruitment of immune cells (e.g.…”

Section: Introductionmentioning

confidence: 99%

Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated Trp53 and Pten in Proximal Tubular Kidney Epithelial Cells

et al. 2021

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Renal cell carcinoma (RCC) is one of the most common urologic malignancies with the highest mortality rates worldwide. However, relevant mouse models that recapitulated the genetic alterations in found in RCC have been lacking. In this study, we crossed Trp53 and Pten conditional knockout mice with Ggt1-Cre mice to generate a Ggt1-Cre; Trp53 LoxP/LoxP ; Pten LoxP/LoxP ; YFP LoxP/LoxP (GPPY) mouse model, which resulted in the formation of dysplastic lesions involving kidney tubular epithelial cells (TEC) with only ~25% of mice developing RCC at an advanced age. Combining CRISPR/Cas9-mediated Vhl knockout in these mice increased the frequency of dysplasia but failed to increase the incidence of RCC. Assessments of whether ischemic injury of TECs in the GPPY kidney without Vhl knockout influences the emergence of RCC revealed that advanced RCC predominantly emerged in the contralateral, non-injured kidney with 100% penetrance at a younger age but rarely in the injured kidney due to severely damaged ischemic TEC. Injured TEC released CXCL1 into the microenvironment that traveled systemically to activate fibroblasts and recruit neutrophils to enable emergence of RCC in the contralateral kidney. Fibroblasts responded to CXCL1 via CXCR2 and recruited tumor-associated neutrophils, which in turn mediated tumor-promoting inflammation and angiogenesis. Treatment with anti-CXCR2 antibodies abolished the emergence of malignant RCC. Collectively, these results demonstrate a defining functional role of systemic inflammation and microenvironment in the emergence of malignant cancer from pre-established dysplastic precursor lesions.Significance: These results identify a role for CXCL1/CXCR2 and the tumor microenvironment in the development of RCC.

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Role of Renal Hypoxia in the Progression From Acute Kidney Injury to Chronic Kidney Disease

Cited by 58 publications

References 149 publications

Inhibition of IRE1/JNK pathway in HK‐2 cells subjected to hypoxia‐reoxygenation attenuates mesangial cells‐derived extracellular matrix production

Inhibition of IRE1/JNK pathway in HK‐2 cells subjected to hypoxia‐reoxygenation attenuates mesangial cells‐derived extracellular matrix production

T helper 17 cells in the pathophysiology of acute and chronic kidney disease

Acute Kidney Injury Instigates Malignant Renal Cell Carcinoma via CXCR2 in Mice with Inactivated Trp53 and Pten in Proximal Tubular Kidney Epithelial Cells

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