Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

Johnson, Bryce G.; Dang, Lan; Marsh, Graham; Roach, Allie M.; Levine, Zebulon G.; Monti, Anthony; Reyon, Deepak; Feigenbaum, Lionel; Duffield, Jeremy S.

doi:10.1172/jci93817

Cited by 56 publications

(77 citation statements)

References 111 publications

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“…As for the normal surgical specimens that were dissected from patients with RCC, the TFF3 expression was detectable in all portions of the urinary tract with peaks in the renal medulla and the urethra . Immunostaining of serial sections with TFF3 and UMOD antibodies revealed that the renal TFF3 protein was located in almost the same area as UMOD, which is specifically expressed in the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule . Our mRNA expression analysis demonstrated that TFF3 was synthesized in the renal tissue and that the level was associated with the urinary TFF3 concentration, which was also associated with the urinary markers of interstitial injury.…”

Section: Discussionmentioning

confidence: 79%

“…18 Immunostaining of serial sections with TFF3 and UMOD antibodies revealed that the renal TFF3 protein was located in almost the same area as UMOD, which is specifically expressed in the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. 19,20 Our mRNA expression analysis demonstrated that TFF3 was synthesized in the renal tissue and that the level was associated with the urinary TFF3 concentration, which was also associated with the urinary markers of interstitial injury. The biopsy specimens used for the mRNA analysis were mainly obtained from the cortex, in close proximity to the medulla, including the outer stripe of the outer medulla.…”

Section: Discussionmentioning

confidence: 83%

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Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

et al. 2018

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AimTrefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN).MethodsWe investigated the renal mRNA expression of TFF3 by real‐time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively.ResultsThe renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients.ConclusionRenal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 83%

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

et al. 2018

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“…There is now clear evidence that ER stress targets renal cells and actively participate in the development of AKI and progression to CKD. Notably, transducers of the UPR, like the IRE1α‐sXBP1 axis, or the PERK‐CHOP pathways play a critical role in mediating the response to ER stress upon kidney injuries to cell death, inflammation and fibrogenesis [El Karoui et al., ; Fan et al., ; Inagi et al., ; Johnson et al., ; Mami et al., ; Mami et al., ]. A wide range of biological disturbances, virtually all of which are encountered upon AKI, induce ER stress, including increased levels of protein synthesis, deficient autophagy, energy deprivation, excess or limited nutrients, deregulated calcium levels, perturbations of redox homeostasis, inflammatory challenges and hypoxia [Wang and Kaufman, ].…”

Section: The Unfolded Protein Response Is An Adaptive Response Activamentioning

confidence: 99%

“…Evidence for the role of ER stress in the progression of CKD mediated by tubular cell apoptosis, inflammation and fibrosis come from mouse carrying the equivalent of the human UMOD mutation denoted as p.Cys147Trp, into the endogenous UMOD [Johnson et al., ]. These mice develop chronic kidney disease at 24 weeks and accumulate UMOD in the ER with extensive interstitial fibrosis and tubular cell death.…”

Section: Er Stress In the Progression Of Chronic Kidney Diseasementioning

confidence: 99%

Endoplasmic reticulum stress and kidney dysfunction

Gallazzini

Pallet

2018

Biology of the Cell

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Chronic kidney disease (CKD) affects millions of persons worldwide and constitutes a major public health problem. Therefore, understanding the molecular basis of CKD is a key challenge for the development of preventive and therapeutic strategies. A major contributor to chronic histological damage associated with CKD is acute kidney injury (AKI). At the cellular level, kidney injuries are associated with microenvironmental alterations, forcing cells to activate adaptive biological processes that eliminate the stressor and generate alarm signals. These signalling pathways actively participate in tissue remodelling by promoting inflammation and fibrogenesis, ultimately leading to CKD. Many stresses that are encountered upon kidney injury are prone to trigger endoplasmic reticulum (ER) stress. In the kidney, ER stress both participates in acute and chronic histological damages, but also promotes cellular adaptation and nephroprotection. In this review, we will discuss the implication of ER stress in the pathophysiology of AKI and CKD progression, and we will give a critical analysis of the current experimental and clinical evidence that support ER stress as a mediator of kidney damage.

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“…In addition, TRIB3 may act as an intrinsic ER stress-mediated cell death mediator to sensitize UMOD-producing tubular cells to TNF (tumor necrosis factor) and TRAIL (TNF-related apoptosis-inducing ligand)-induced apoptosis. Most importantly, when the mutant mice are treated with the soluble recombinant fusion protein TNF receptor:Fc, a TNFα signaling antagonizer, ER stress-mediated inflammation, apoptosis and fibrosis are attenuated with improvement in renal function [43]. …”

Section: Tubular Er Stress and Autosomal Dominant Tubulointerstitial mentioning

confidence: 99%

Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

Park

Chen

2018

Pediatr Nephrol

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The advent of next-generation sequencing (NGS) in recent years has led to a rapid discovery of novel or rare genetic variants in human kidney cell genes, which is transforming the risk assessment, diagnosis, and treatment of kidney disease. Mutations may lead to protein misfolding, disruption of protein trafficking, and endoplasmic reticulum (ER) retention. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and unfolded protein response. Mutations in nephrin (NPHS1), podocin (NPHS2), laminin β2 (LAMB2), and α-actinin-4 (ACTN4) have been shown to induce ER stress in HEK293 cells and podocytes in hereditary nephrotic syndromes; various founder mutations in collagen IV α chains (COL4A) have been demonstrated to activate podocyte ER stress in collagen IV nephropathies; and mutations in uromodulin (UMOD) have been reported to trigger tubular ER stress in autosomal dominant tubulointerstitial kidney disease. Meanwhile, ER resident protein SEC63 may modify disease severity in autosomal dominant polycystic kidney disease. These findings underscore the importance of ER stress in the pathogenesis of monogenic kidney disease. Recently, we have identified mesencephalic astrocyte-derived neurotrophic factor (MANF) and cysteine-rich with EGF-like domains 2 (CRELD2) as urinary ER stress biomarkers in ER stress-mediated kidney diseases.

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Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis

Cited by 56 publications

References 111 publications

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy

Endoplasmic reticulum stress and kidney dysfunction

Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

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