Neonatal obstructive nephropathy induces necroptosis and necroinflammation

Popper, Bastian; Rammer, Marian Theodor; Gasparitsch, Mojca; Singer, Teresa; Keller, U.; Döring, Yvonne; Lange-Sperandio, Bärbel

doi:10.1038/s41598-019-55079-w

Cited by 21 publications

(38 citation statements)

References 52 publications

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“…IL-33 is able to activate basophils and eosinophils, as well as to induce type 2 immune responses (58). Recently it was shown that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with ureteral obstruction (17). Biochemical analyses showed a decrease in caspase-8 expression and an increase in RIPK3 and pMLKL expression, indicating a role of necroptosis in UUO.…”

Section: Il-1a and Il-33mentioning

confidence: 99%

DAMPs in Unilateral Ureteral Obstruction

Wyczanska

Lange-Sperandio

2020

Front. Immunol.

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Damage-associated molecular patterns (DAMPs) are released from tubular and interstitial cells in the kidney after unilateral ureteral obstruction (UUO). DAMPs are recognized by pattern recognition receptors (PRRs), which mediate the initiation of an immune response and the release of inflammatory cytokines. The animal model of UUO is used for various purposes. UUO in adult mice serves as a model for accelerated renal fibrosis, which is a hallmark of progressive renal disease. UUO in adult mice enables to study cell death, inflammation, and extracellular matrix deposition in the kidney. Neonatal UUO is a model for congenital obstructive nephropathies. It studies inflammation, apoptosis, and interstitial fibrosis in the neonatal kidney, when nephrogenesis is still ongoing. Following UUO, several DAMPs as well as DAMP receptors are upregulated. In adult UUO, soluble uric acid is upregulated and activates the NOD-like receptor family, pyrin domain containing-3 (NLRP3) inflammasome, which promotes fibrosis, apoptosis, and reactive oxygen species (ROS) injury. Further DAMPs associated with UUO are uromodulin, members of the IL-1 family, and necrotic cell DNA, all of which promote sterile inflammation. In neonatal UUO, the receptor for advanced glycation endproducts (RAGE) is highly upregulated. RAGE is a ligand for several DAMPs, including high mobility group box 1 (HMGB1) and S100 proteins, which play an important role in renal fibrosis. Additionally, necroptosis is an important mechanism of cell death, besides apoptosis, in neonatal UUO. It is highly inflammatory due to release of cytokines and specific DAMPs. The release and recognition of DAMPs initiate sterile inflammation, which makes them good candidates to develop and improve diagnostic and therapeutic strategies in renal fibrosis and congenital obstructive nephropathies.

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Section: Il-1a and Il-33mentioning

confidence: 99%

DAMPs in Unilateral Ureteral Obstruction

Wyczanska

Lange-Sperandio

2020

Front. Immunol.

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“…As UMOD accumulation within renal tubules has been reported during normal neonatal development, we investigated UMOD expression in neonatal kidneys after unilateral ureteral obstruction (UUO) thereby linking a potential accumulation of UMOD at extratubular sites to leukocyte infiltration, which is commonly observed in neonatal UUO (37,38). First, we performed Western Blot analysis in sham (control) and UUO operated neonatal kidneys.…”

Section: Neonatal Obstructive Nephropathy Induces Intra-and Extratubumentioning

confidence: 99%

“…UMOD is highly expressed in the developing kidney and urinary tract obstruction during kidney development leads to leukocyte recruitment, inflammation and interstitial fibrosis in the neonatal kidney (37,54). Therefore, we investigated UMOD expression, localization and immune cell infiltration in a neonatal model of unilateral ureteral obstruction (UUO).…”

Section: Neonatal Obstructive Nephropathy Induces Intra-and Extratubumentioning

confidence: 99%

“…Newborn WT mice were subjected to complete left ureteral obstruction (UUO) or sham operation under general anesthesia with isoflurane and oxygen at the second day of life as described before (37,54,60). After recovery, neonatal mice were returned to their mothers until sacrifice at day 3, 7, 14, or 21 of life.…”

Section: Animal Model Of Unilateral Ureteral Obstructionmentioning

confidence: 99%

“…Kidney sections were stained with periodic acid Schiff (PAS) to investigate tubular atrophy in UUO and sham-operated mice as described previously (37,54,60). Alterations of the tubular basement membrane (TBM) were determined in 20 sequentially selected fields at x400 magnification.…”

Section: Pas Staining Of Sham and Uuo Operated Neonatal Kidneysmentioning

confidence: 99%

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Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo

Immler¹,

Lange-Sperandio

Steffen³

et al. 2020

Preprint

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Uromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) within the lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitment in vivo and led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD did not directly upregulate adhesion molecules on endothelial cells and did not directly activate β2 integrins on neutrophils. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.

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The progression of obstructive renal fibrosis in rats is regulated by ADAMTS18 gene methylation in the embryonic kidney through the AKT/Notch pathway

Xu,

Zhang,

et al. 2023

J Biochem & Molecular Tox

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This study aimed to explore the mechanism by which postembryonic renal ADAMTS18 methylation influences obstructive renal fibrosis in rats. After exposure to transforming growth factor (TGF)‐β1 during the embryonic period, analysis of postembryonic renal ADAMTS18 methylation and expression levels was conducted. Histological analysis was performed to assess embryonic kidney lesions and damage. Western blot analysis was used to determine the expression of renal fibrosis markers. Rats with ureteral obstruction and a healthy control group were selected. The methylation levels of ADAMTS18 in the different groups were analyzed. Western blot analysis and immunohistochemistry were performed to analyze the expression of renal fibrosis markers, and kidney‐related indicators were measured. Treatment with TGF‐β1 resulted in abnormal development of the postembryonic kidney, which was characterized by rough kidney surfaces with mild depressions and irregularities on the outer surface. TGF‐β1 treatment significantly promoted ADAMTS18 methylation and activated the protein kinase B (AKT)/Notch pathway. Ureteral obstruction was induced to establish a renal hydronephrosis model, which led to renal fibrotic injury in newborn rats. Overexpression of the ADAMTS18 gene alleviated renal fibrosis. The western blot results showed that compared to that in the control group, the expression of renal fibrosis markers was significantly decreased after ADAMTS18 overexpression, and there was a thicker renal parenchymal tissue layer and significantly reduced p‐AKT/AKT and Notch1 levels. TGF‐β1 can induce ADAMTS18 gene methylation in the postembryonic kidney, and the resulting downregulation of ADAMTS18 expression has long‐term effects on kidney development, potentially leading to increased susceptibility to obstructive renal fibrosis. This mechanism may involve activation of the AKT/Notch pathway. Reversing ADAMTS18 gene methylation may reverse this process.

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Neonatal obstructive nephropathy induces necroptosis and necroinflammation

Cited by 21 publications

References 52 publications

DAMPs in Unilateral Ureteral Obstruction

DAMPs in Unilateral Ureteral Obstruction

Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo

The progression of obstructive renal fibrosis in rats is regulated by ADAMTS18 gene methylation in the embryonic kidney through the AKT/Notch pathway

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