scholarly journals Zebrafish mesonephric renin cells are functionally conserved and comprise two distinct morphological populations

2017 ◽  
Vol 312 (4) ◽  
pp. F778-F790 ◽  
Author(s):  
Sebastien A. Rider ◽  
Helen C. Christian ◽  
Linda J. Mullins ◽  
Amelia R. Howarth ◽  
Calum A. MacRae ◽  
...  
Keyword(s):  
Renal Injury ◽  
Secretory Granules ◽  
Smooth Muscle Actin ◽  
Renin Angiotensin System ◽  
Transcriptional Responses ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Perivascular Cell ◽  
Ultrastructural Studies ◽  
Injury And Repair

Zebrafish provide an excellent model in which to assess the role of the renin-angiotensin system in renal development, injury, and repair. In contrast to mammals, zebrafish kidney organogenesis terminates with the mesonephros. Despite this, the basic functional structure of the nephron is conserved across vertebrates. The relevance of teleosts for studies relating to the regulation of the renin-angiotensin system was established by assessing the phenotype and functional regulation of renin-expressing cells in zebrafish. Transgenic fluorescent reporters for renin ( ren), smooth muscle actin ( acta2), and platelet-derived growth factor receptor-beta ( pdgfrb) were studied to determine the phenotype and secretory ultrastructure of perivascular renin-expressing cells. Whole kidney ren transcription responded to altered salinity, pharmacological renin-angiotensin system inhibition, and renal injury. Mesonephric ren-expressing cells occupied niches at the preglomerular arteries and afferent arterioles, forming intermittent epithelioid-like multicellular clusters exhibiting a granular secretory ultrastructure. In contrast, renin cells of the efferent arterioles were thin bodied and lacked secretory granules. Renin cells expressed the perivascular cell markers acta2 and pdgfrb. Transcriptional responses of ren to physiological challenge support the presence of a functional renin-angiotensin system and are consistent with the production of active renin. The reparative capability of the zebrafish kidney was harnessed to demonstrate that ren transcription is a marker for renal injury and repair. Our studies demonstrate substantive conservation of renin regulation across vertebrates, and ultrastructural studies of renin cells reveal at least two distinct morphologies of mesonephric perivascular ren-expressing cells.

scholarly journals Alisol B 23-acetate attenuates CKD progression by regulating the renin–angiotensin system and gut–kidney axis

2020 ◽  
Vol 11 ◽  
pp. 204062232092002
Author(s):  
Hua Chen ◽  
Min-Chang Wang ◽  
Yuan-Yuan Chen ◽  
Lin Chen ◽  
Yan-Ni Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Gut Microbiome ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Renin Angiotensin System ◽  
Ckd Progression ◽  
Angiotensin System ◽  
Mesenchymal Transition ◽  
Renin Angiotensin

Background: Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin–angiotensin system (RAS) in preventing CKD progression are limited. Methods: In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS. Results: ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-β (TGF-β)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/β-catenin and mitochondrial-associated caspase pathways. Conclusion: These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

2012 ◽  
Vol 303 (7) ◽  
pp. F1037-F1048 ◽  
Author(s):  
Christoph Fraune ◽  
Sascha Lange ◽  
Christian Krebs ◽  
Alexandra Hölzel ◽  
Jana Baucke ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Plasma Concentrations ◽  
Renin Angiotensin System ◽  
Pivotal Role ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Renin Inhibition

The role of the renin-angiotensin system in chronic kidney disease involves multiple peptides and receptors. Exerting antipodal pathophysiological mechanisms, renin inhibition and AT1 antagonism ameliorate renal damage. However, it is unclear which mechanism exerts better nephroprotection. We compared the renin inhibitor aliskiren with the AT1 antagonist losartan in mice with chronic kidney disease due to renal ablation. Doses were adjusted to equipotent inhibition of the renin-angiotensin system, determined via a dose-response quantifying plasma and renal renin expression. Six-week treatment with either 500 mg/l drinking water losartan or 50 mg·kg−1·day−1 aliskiren significantly decreased albuminuria, glomerular damage, and transcription rates of renal injury markers to a similar extent. An array analysis comparing renal gene expression of losartan- and aliskiren-treated mice evaluating >34,000 transcripts demonstrated regulation for 14 genes only, with small differences. No superior nephroprotection was found by combining losartan and aliskiren. Compared with plasma concentrations, aliskiren accumulated ∼7- to 29-fold in the heart, liver, lung, and spleen and ∼156-fold in the kidney. After withdrawal, plasma concentrations dropped to zero within 24 h, whereas renal tissue concentrations declined slowly over days. Withdrawal of aliskiren in mice with chronic kidney disease revealed a significantly delayed re-increase in albuminuria compared with withdrawal of losartan. This study demonstrates equieffective nephroprotection of renin inhibition and AT1 antagonism in mice with chronic kidney disease without additional benefit of combination therapy. These observations underscore the pivotal role of targeting ANG II to reduce renal injury.

Blockade of renin-angiotensin system ameliorates renal injury in NIDDM model rats

2000 ◽  
Vol 4 (3) ◽  
pp. 207-214 ◽  
Author(s):  
M. Ohta ◽  
H. Nagano ◽  
M. Noda ◽  
T. Matsuo ◽  
H. Yamasaki ◽  
...  
Keyword(s):  
Renal Injury ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

scholarly journals Secreted protein acidic and rich in cysteine expression after subtotal nephrectomy and blockade of the renin-angiotensin system.

1997 ◽  
Vol 8 (9) ◽  
pp. 1373-1382
Author(s):  
L L Wu ◽  
A Cox ◽  
C J Roe ◽  
M Dziadek ◽  
M E Cooper ◽  
...  
Keyword(s):  
Renal Injury ◽  
De Novo ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Secreted Protein ◽  
Matrix Remodeling ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Subtotal Nephrectomy ◽  
Gene And Protein Expression

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix-associated protein with antiadhesive, antiproliferative, and matrix remodeling properties. SPARC gene and protein expression were investigated after subtotal nephrectomy (STNx), a model of noninflammatory progressive renal injury. In addition, the effect of blockade of the renin-angiotensin system by the angiotensin-converting enzyme inhibitor ramipril or by the angiotensin II receptor antagonist valsartan was examined. The STNx rats developed hypertension, proteinuria, and renal impairment. These changes were associated with a 2.4-fold increase in SPARC gene expression in STNx compared with SHAM kidneys (P < 0.001). In situ hybridization revealed increased SPARC mRNA in glomeruli and interstitial cells, as well as de novo expression by tubular epithelial cells at sites of renal injury. Immunofluorescence studies confirmed concordant changes in SPARC protein. Both ramipril and valsartan ameliorated renal injury and significantly reduced SPARC overexpression in the STNx animals. The findings of the present study suggest that SPARC, in the context of its known biological actions, may influence some of the pathological features associated with significant renal mass reduction.

Renin–angiotensin system inhibition ameliorates CCl4-induced liver fibrosis in mice through the inactivation of nuclear transcription factor kappa B

2018 ◽  
Vol 96 (6) ◽  
pp. 569-576 ◽  
Author(s):  
Sameh Saber ◽  
Amr A.A. Mahmoud ◽  
Noha S. Helal ◽  
Eman El-Ahwany ◽  
Rasha H. Abdelghany
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Smooth Muscle Actin ◽  
Renin Angiotensin System ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Nuclear Transcription Factor ◽  
Ras Inhibitors

Therapeutic interventions for liver fibrosis are still limited due to the complicated molecular pathogenesis. Renin–angiotensin system (RAS) seems to contribute to the development of hepatic fibrosis. Therefore, we aimed to examine the effect of RAS inhibition on CCl4-induced liver fibrosis. Mice were treated with silymarin (30 mg·kg−1), perindopril (1 mg·kg−1), fosinopril (2 mg·kg−1), or losartan (10 mg·kg−1). The administration of RAS inhibitors improved liver histology and decreased protein expression of alpha smooth muscle actin (α-SMA) and hepatic content of hydroxyproline. These effects found to be mediated via inactivation of nuclear transcription factor kappa B (NFκB) pathway by the inhibition of NFκB p65 phosphorylation at the Ser536 residue and phosphorylation-induced degradation of nuclear factor kappa-B inhibitor alpha (NFκBia) subsequently inhibited NFκB-induced TNF-α and TGF-β1, leading to lower levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF). We concluded that the tissue affinity of the angiotensin converting enzyme inhibitors (ACEIs) has no impact on its antifibrotic activity and that interfering the RAS either through the inhibition of ACE or the blockade of AT1R has the same therapeutic benefit. These results suggest RAS inhibitors as promising candidates for further clinical trials in the management of hepatic fibrosis.

scholarly journals Comparative Studies of Renin-Null Zebrafish and Mice Provide New Functional Insights

Hypertension ◽  
2022 ◽  
Author(s):  
Scott Hoffmann ◽  
Linda Mullins ◽  
Sebastien Rider ◽  
Cara Brown ◽  
Charlotte B. Buckley ◽  
...  
Keyword(s):  
Cell Function ◽  
Smooth Muscle Actin ◽  
Larval Growth ◽  
Renin Angiotensin System ◽  
Sequencing Analysis ◽  
Renal Vasculature ◽  
Exon 2 ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Larval Stages

Background: The renin-angiotensin system is highly conserved across vertebrates, including zebrafish, which possess orthologous genes coding for renin-angiotensin system proteins, and specialized mural cells of the kidney arterioles, capable of synthesising and secreting renin. Methods: We generated zebrafish with CRISPR-Cas9-targeted knockout of renin ( ren −/− ) to investigate renin function in a low blood pressure environment. We used single-cell (10×) RNA sequencing analysis to compare the transcriptome profiles of renin lineage cells from mesonephric kidneys of ren −/− with ren +/+ zebrafish and with the metanephric kidneys of Ren1 c−/− and Ren1 c +/+ mice. Results: The ren −/− larvae exhibited delays in larval growth, glomerular fusion and appearance of a swim bladder, but were viable and withstood low salinity during early larval stages. Optogenetic ablation of renin-expressing cells, located at the anterior mesenteric artery of 3-day-old larvae, caused a loss of tone, due to diminished contractility. The ren −/− mesonephric kidney exhibited vacuolated cells in the proximal tubule, which were also observed in Ren1 c−/− mouse kidney. Fluorescent reporters for renin and smooth muscle actin ( tg(ren:LifeAct-RFP; acta2:EGFP )), revealed a dramatic recruitment of renin lineage cells along the renal vasculature of adult ren −/− fish, suggesting a continued requirement for renin, in the absence of detectable angiotensin metabolites, as seen in the Ren1 YFP Ren1 c−/− mouse. Both phenotypes were rescued by alleles lacking the potential for glycosylation at exon 2, suggesting that glycosylation is not essential for normal physiological function. Conclusions: Phenotypic similarities and transcriptional variations between mouse and zebrafish renin knockouts suggests evolution of renin cell function with terrestrial survival.

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