Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice

Kubik, Melanie J.; Wyczanska, Maja; Gasparitsch, Mojca; Keller, U.; Weber, Stefanie; Schaefer, Franz; Lange-Sperandio, Bärbel

doi:10.1038/s41598-020-76328-3

Cited by 6 publications

(4 citation statements)

References 67 publications

(93 reference statements)

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“…After 24 h of embryonic kidney obstruction, certain developmental genes are immediately regulated, which indicates that these genes can directly stimulate their developmental program, whereas adult kidneys only show partial gene dysregulation after continuous damage for more than 2 weeks. [ 2 ] Adverse events during embryonic life, such as malnutrition, exposure to ethanol, drug use, and exposure to glucocorticoids, may cause permanent kidney changes. [ 18 ] Prenatal exposure to TGF‐β1 may cause kidney damage, but the specific mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…[1] The occurrence and development of congenital obstructive renal disease result from an interaction between genetic and nongenetic factors. [2] Histologically, congenital obstructive renal disease is characterized by poor renal development, interstitial fibrosis, compensatory growth in the contralateral kidney, renal pelvic dilation, and increased intrarenal pressure. [3] The most common cause of CAKUT is ureteropelvic junction obstruction (UPJO) (10%-30%).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…In Il-10 −/− mice cDC1 and CD11b hi cells show a delayed infiltration into the obstructed kidney in comparison to WT, which emphasizes the possibility of a still unknown function of IL-10 in the development of the immune system during the neonatal period. In neonatal UUO, nephrogenesis is still ongoing with constant changes in gene regulation and composition of the immune system in the kidney 46 , 53 . Even under basal conditions several of our markers already show diminished expression in Il-10 −/− mice compared to WT.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 enhances recruitment of immune cells in the neonatal mouse model of obstructive nephropathy

Wyczanska,

Thalmeier,

Keller

et al. 2024

Sci Rep

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Urinary tract obstruction during renal development leads to inflammation, leukocyte infiltration, tubular cell death, and interstitial fibrosis. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, produced mainly by monocytes/macrophages and regulatory T-cells. IL-10 inhibits innate and adaptive immune responses. IL-10 has a protective role in the adult model of obstructive uropathy. However, its role in neonatal obstructive uropathy is still unclear which led us to study the role of IL-10 in neonatal mice with unilateral ureteral obstruction (UUO). UUO serves as a model for congenital obstructive nephropathies, a leading cause of kidney failure in children. Newborn Il-10−/− and C57BL/6 wildtype-mice (WT) were subjected to complete UUO or sham-operation on the 2nd day of life. Neonatal kidneys were harvested at day 3, 7, and 14 of life and analyzed for different leukocyte subpopulations by FACS, for cytokines and chemokines by Luminex assay and ELISA, and for inflammation, programmed cell death, and fibrosis by immunohistochemistry and western blot. Compared to WT mice, Il-10−/− mice showed reduced infiltration of neutrophils, CD11bhi cells, conventional type 1 dendritic cells, and T-cells following UUO. Il-10−/− mice with UUO also showed a reduction in pro-inflammatory cytokine and chemokine release compared to WT with UUO, mainly of IP-10, IL-1α, MIP-2α and IL-17A. In addition, Il-10−/− mice showed less necroptosis after UUO while the rate of apoptosis was not different. Finally, α-SMA and collagen abundance as readout for fibrosis were similar in Il-10−/− and WT with UUO. Surprisingly and in contrast to adult Il-10−/− mice undergoing UUO, neonatal Il-10−/− mice with UUO showed a reduced inflammatory response compared to respective WT control mice with UUO. Notably, long term changes such as renal fibrosis were not different between neonatal Il-10−/− and neonatal WT mice with UUO suggesting that IL-10 signaling is different in neonates and adults with UUO.

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“…Similar changes in renin lineage cells have also been reported in adult mice in response to glomerular and podocyte injury 12,[43][44][45][46] and vascular hypertrophy during chronic stimulation of renin cells. 15,16 The increased cellular proliferation triggered by a ureteral obstruction in neonatal 2,47 and adult UUO models 12,48 may be attributed to cellular reprogramming and cell fate changes leading to the expansion of the CoRL during persistent obstructive injury.…”

Section: Discussionmentioning

confidence: 99%

Cells of the renin lineage promote kidney regeneration post‐release of ureteral obstruction in neonatal mice

Nagalakshmi

Liang

et al. 2023

Acta Physiologica

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Aim: Ureteral obstruction leads to significant changes in kidney renin expression. It is unclear whether those changes are responsible for the progression of kidney damage, repair, or regeneration. In the current study, we aimed to elucidate the contribution of renin-producing cells (RPCs) and the cells of the renin lineage (CoRL) towards kidney damage and regeneration using a model of partial and reversible unilateral ureteral obstruction (pUUO) in neonatal mice. Methods: Renin cells are progenitors for other renal cell types collectively calledCoRL. We labeled the CoRL with green fluorescent protein (GFP) using genetic approaches. We performed lineage tracing to analyze the changes in the distribution of CoRL during and after the release of obstruction. We also ablated the RPCs and CoRL by cell-specific expression of Diphtheria Toxin Sub-unit A (DTA).Finally, we evaluated the kidney damage and regeneration during and after the release of obstruction in the absence of CoRL. Results:In the obstructed kidneys, there was a 163% increase in the reninpositive area and a remarkable increase in the distribution of GFP + CoRL. Relief of obstruction abrogated these changes. In addition, DTA-expressing animals did not respond to pUUO with increased RPCs and CoRL. Moreover, reduction in CoRL significantly compromised the kidney's ability to recover from the damage after the release of obstruction.Conclusions: CoRL play a role in the regeneration of the kidneys post-relief of obstruction.

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Renal developmental genes are differentially regulated after unilateral ureteral obstruction in neonatal and adult mice

Cited by 6 publications

References 67 publications

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

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

Interleukin-10 enhances recruitment of immune cells in the neonatal mouse model of obstructive nephropathy

Cells of the renin lineage promote kidney regeneration post‐release of ureteral obstruction in neonatal mice

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