SuO028GENETIC TESTING REVEALS INCREASED PREVALENCE OF UROMODULIN ASSOCIATED KIDNEY DISEASE

Gast, Christine; Marinaki, Tony; Arenas-Hernandez, Monica; Campbell, S. A.

doi:10.1093/ndt/gfv160.05

Cited by 5 publications

(4 citation statements)

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“…6 Section of Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. 7 Research Unit of Rare Diseases, Department of Pediatric and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, Prague, Czech Republic. 8 Pfizer Worldwide Research and Development, Inflammation & Immunology, Cambridge, MA, USA.…”

Section: Reporting Summarymentioning

confidence: 99%

“…ADTKD-UMOD is a monogenic form of renal tubulointerstitial fibrosis and chronic kidney disease (CKD), which occurs in ∼10% of the population associated with significant morbidity and mortality 6 . ADTKD also represents as many as 25% of patients with inherited kidney disease, after exclusion of polycystic kidney disease and Alport syndrome 7 . Uromodulin (Tamm-Horsfall protein) is largely expressed in the thick ascending limb (TAL) tubular epithelial cells.…”

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confidence: 99%

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MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Kim,

Li,

et al. 2023

Nat Commun

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Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse model. Conversely, genetic ablation of MANF in the mutant thick ascending limb tubular cells worsens autophagy suppression and kidney fibrosis. Together, we have discovered MANF as a biotherapeutic protein and elucidated previously unknown mechanisms of MANF in the regulation of organelle homeostasis, which may have broad therapeutic applications to treat various proteinopathies.

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Section: Reporting Summarymentioning

confidence: 99%

mentioning

confidence: 99%

MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Kim,

Li,

et al. 2023

Nat Commun

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“…It represents as many as 25% of patients with inherited kidney disease, after exclusion of polycystic kidney disease and AS [33]. ADTKD is caused by mutations in UMOD , MUC1 , REN and HNF1B .…”

Section: Tubular Er Stress and Autosomal Dominant Tubulointerstitial mentioning

confidence: 99%

“…ADTKD is a monogenic form of renal tubulointerstitial fibrosis leading to chronic kidney disease. It represents as many as 25% of patients with inherited kidney disease, after exclusion of polycystic kidney disease and AS [33]. ADTKD is caused by mutations in UMOD , MUC1 , REN and HNF1B .…”

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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From juvenile hyperuricaemia to dysfunctional uromodulin: an ongoing metamorphosis

Gast

Fairbanks

2016

Pediatr Nephrol

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Familial juvenile hyperuricaemic nephropathy (FJHN) is a diagnosis that is easily missed. It has taken a long time to clarify the pathophysiology and prevalence of this disease entity which has been shown to be genetically identical to medullary cystic kidney disease (MCKD) type II. The initial suspicion that uric acid was the noxious agent has been replaced by the recognition that a mutant uromodulin (UMOD) is the real culprit-although the exact mechanisms of pathogenicity remain uncertain. The mutation has been traced to the UMOD gene in chromosome 16. The disease is characterised by the classic triad of autosomal dominant inheritance, progressive renal failure beginning in the third to fifth decade of life and gout. Phenotypically similar but genotypically distinct entities have been described over the last 10 years, making a clinical diagnosis difficult. These include mutations in the renin, hepatocyte nuclear factor 1-β and mucin 1 genes. UMOD-associated kidney disease has been proposed as a logical diagnostic label to replace FJHN, but given all these other mutations, an over-arching diagnostic term of 'autosomal dominant tubulointerstitial kidney disease' (ADTKD) has been recently adopted. Allopurinol has been suggested as a therapeutic agent, but unfortunately this was based on non-randomised uncontrolled trials with small patient numbers.

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SuO028GENETIC TESTING REVEALS INCREASED PREVALENCE OF UROMODULIN ASSOCIATED KIDNEY DISEASE

Cited by 5 publications

References 0 publications

MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

MANF stimulates autophagy and restores mitochondrial homeostasis to treat autosomal dominant tubulointerstitial kidney disease in mice

Endoplasmic reticulum stress and monogenic kidney diseases in precision nephrology

From juvenile hyperuricaemia to dysfunctional uromodulin: an ongoing metamorphosis

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