CD103+ Dendritic Cells Elicit CD8+ T Cell Responses to Accelerate Kidney Injury in Adriamycin Nephropathy

Cao, Qi; Lu, Junyu; Li, Qing; Wang, Changqi; Wang, Xin Maggie; Lee, Vincent; Wang, Chengshi; Nguyen, Hanh; Zheng, Guoping; Zhao, Ye; Alexander, Stephen I.; Wang, Yiping; Harris, David C.H.

doi:10.1681/asn.2015030229

Cited by 52 publications

(48 citation statements)

References 59 publications

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“…Thus, the relevance of Treg/Th17 responses is context‐dependent and the role of CCL20 may differ for different disease entities. The presently observed evidence for CCL20 nephroprotection in FA‐AKI is likely dependent on reduced renal Treg infiltration rather than on reduced Th17 influx, while potentially deleterious Th1 and CD8 + responses were preserved . CCR6 is also expressed in innate immune cells, such as neutrophils and macrophages, and the effects of CCL20 neutralisation may extend beyond T‐cell migration.…”

Section: Discussionmentioning

confidence: 87%

CCL20 blockade increases the severity of nephrotoxic folic acid‐induced acute kidney injury

González‐Guerrero

Morgado‐Pascual

Cannata‐Ortiz

et al. 2018

The Journal of Pathology

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The chemokine CCL20 activates the CCR6 receptor and has been implicated in the pathogenesis of glomerular injury. However, it is unknown whether it contributes to acute kidney injury (AKI). We identified CCL20 as upregulated in a systems biology strategy combining transcriptomics of kidney tissue from experimental toxic folic acid-induced AKI and from stressed cultured tubular cells and have explored the expression and function of CCL20 in experimental and clinical AKI. CCL20 upregulation was confirmed in three models of kidney injury induced by a folic acid overdose, cisplatin or unilateral ureteral obstruction. In injured kidneys, CCL20 was expressed by tubular, endothelial, and interstitial cells, and was also upregulated in human kidneys with AKI. Urinary CCL20 was increased in human AKI and was associated with severity. The function of CCL20 in nephrotoxic folic acid-induced AKI was assessed by using neutralising anti-CCL20 antibodies or CCR6-deficient mice. CCL20/CCR6 targeting increased the severity of kidney failure and mortality. This was associated with more severe histological injury, nephrocalcinosis, capillary rarefaction, and fibrosis, as well as higher expression of tubular injury-associated genes. Surprisingly, mice with CCL20 blockade had a lower tubular proliferative response and a higher number of cells in the G2/M phase, suggesting impaired repair mechanisms. This may be related to a lower influx of Tregs, despite a milder inflammatory response in terms of chemokine expression and infiltration by IL-17 cells and neutrophils. In conclusion, CCL20 has a nephroprotective role during AKI, both by decreasing tissue injury and by facilitating repair. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 87%

CCL20 blockade increases the severity of nephrotoxic folic acid‐induced acute kidney injury

González‐Guerrero

Morgado‐Pascual

Cannata‐Ortiz

et al. 2018

The Journal of Pathology

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“…Ablation of macrophages—or inhibition of macrophage influx—attenuates kidney injury and fibrosis [34–36]. Furthermore, infiltration of CD4 + and CD8 + T-cells seemingly is also important in kidney disease progression [13, 36–39], although contradictory results regarding the role of CD4+ T cells exist [40] and the exact role(s) played by inflammatory cells in kidney fibrosis is not delineated.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

et al. 2016

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Chronic kidney disease (CKD) leads to uremia. CKD is characterized by a gradual increase in kidney fibrosis and loss of kidney function, which is associated with a progressive increase in risk of atherosclerosis and cardiovascular death. To prevent progression of both kidney fibrosis and atherosclerosis in uremic settings, insight into new treatment options with effects on both parameters is warranted. The GLP-1 analogue liraglutide improves glucose homeostasis, and is approved for treatment of type 2 diabetes. Animal studies suggest that GLP-1 also dampens inflammation and atherosclerosis. Our aim was to examine effects of liraglutide on kidney fibrosis and atherosclerosis in a mouse model of moderate uremia (5/6 nephrectomy (NX)). Uremic (n = 29) and sham-operated (n = 14) atherosclerosis-prone low density lipoprotein receptor knockout mice were treated with liraglutide (1000 μg/kg, s.c. once daily) or vehicle for 13 weeks. As expected, uremia increased aortic atherosclerosis. In the remnant kidneys from NX mice, flow cytometry revealed an increase in the number of monocyte-like cells (CD68+F4/80-), CD4+, and CD8+ T-cells, suggesting that moderate uremia induced kidney inflammation. Furthermore, markers of fibrosis (i.e. Col1a1 and Col3a1) were upregulated, and histological examinations showed increased glomerular diameter in NX mice. Importantly, liraglutide treatment attenuated atherosclerosis (~40%, p < 0.05) and reduced kidney inflammation in NX mice. There was no effect of liraglutide on expression of fibrosis markers and/or kidney histology. This study suggests that liraglutide has beneficial effects in a mouse model of moderate uremia by reducing atherosclerosis and attenuating kidney inflammation.

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“…Here, we assessed the effects of ELA32 and its shortest furincleaved fragment ELA11 (ELA [22][23][24][25][26][27][28][29][30][31][32]) ( Figure 1A) on the hypoxia-reperfusion (H/R)-injured renal tubular cells and the renal I/R-injured mice. Cell apoptosis, inflammation, DDR, tubular lesions, and renal function were examined.…”

mentioning

confidence: 99%

ELABELA and an ELABELA Fragment Protect against AKI

Chen

Wang

et al. 2017

JASN

118

133

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Renal ischemia-reperfusion (I/R) injury is the most common cause of AKI, which associates with high mortality and has no effective therapy. ELABELA (ELA) is a newly identified 32-residue hormone peptide highly expressed in adult kidney. To investigate whether ELA has protective effects on renal I/R injury, we administered the mature peptide (ELA32) or the 11-residue furin-cleaved fragment (ELA11) to hypoxia-reperfusion (H/R)-injured or adriamycin-treated renal tubular cells ELA32 and ELA11 significantly inhibited the elevation of the DNA damage response, apoptosis, and inflammation in H/R-injured renal tubular cells and suppressed adriamycin-induced DNA damage response. Similarly, overexpression of ELA32 or ELA11 significantly inhibited H/R-induced cell death, DNA damage response, and inflammation. Notably, treatment of mice with ELA32 or ELA11 but not an ELA11 mutant with a cysteine to alanine substitution at the N terminus (AE11C) inhibited I/R injury-induced renal fibrosis, inflammation, apoptosis, and the DNA damage response and markedly reduced the renal tubular lesions and renal dysfunction. Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI.

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CD103+ Dendritic Cells Elicit CD8+ T Cell Responses to Accelerate Kidney Injury in Adriamycin Nephropathy

Cited by 52 publications

References 59 publications

CCL20 blockade increases the severity of nephrotoxic folic acid‐induced acute kidney injury

CCL20 blockade increases the severity of nephrotoxic folic acid‐induced acute kidney injury

Liraglutide Reduces Both Atherosclerosis and Kidney Inflammation in Moderately Uremic LDLr-/- Mice

ELABELA and an ELABELA Fragment Protect against AKI

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