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.

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.

scholarly journals Role of the renin angiotensin system on bone marrow-derived stem cell function and its impact on skeletal muscle angiogenesis

2010 ◽  
Vol 42 (3) ◽  
pp. 437-444 ◽  
Author(s):  
Micheline M. de Resende ◽  
Timothy J. Stodola ◽  
Andrew S. Greene
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Endothelial Cell ◽  
Cell Function ◽  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
Brown Norway ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin

Autologous bone marrow cell (BMC) transplantation has been shown as a potential approach to treat various ischemic diseases. However, under many conditions BMC dysfunction has been reported, leading to poor cell engraftment and a failure of tissue revascularization. We have previously shown that skeletal muscle angiogenesis induced by electrical stimulation (ES) is impaired in the SS/Mcwi rats and that this effect is related to a dysregulation of the renin angiotensin system (RAS) that is normalized by the replacement of chromosome 13 derived from the Brown Norway rat (SS-13BN/Mcwi consomic rats). The present study explored bone marrow-derived endothelial cell (BM-EC) function in the SS/Mcwi rat and its impact on skeletal muscle angiogenesis induced by ES. SS/Mcwi rats were randomized to receive BMC from: SS/Mcwi; SS-13BN/Mcwi; SS/Mcwi rats infused with saline or ANG II (3 ng·kg−1·min−1). BMC were injected in the stimulated tibialis anterior muscle of SS/Mcwi rats. Vessel density was evaluated in unstimulated and stimulated muscles after 7 days of ES. BMC isolated from SS/Mcwi or SS/Mcwi rats infused with saline failed to restore angiogenesis induced by ES. However, BMC isolated from SS-13BN/Mcwi and SS/Mcwi rats infused with ANG II effectively restored the angiogenesis response in the SS/Mcwi recipient. Furthermore, ANG II infusion increased the capacity of BM-EC to induce endothelial cell tube formation in vitro and slightly increased VEGF protein expression. This study suggests that dysregulation of the RAS in the SS/Mcwi rat contributes to impaired BM-EC function and could impact the angiogenic therapeutic potential of BMC.

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.

Effect of endogenous angiotensin II on the frequency response of the renal vasculature

2004 ◽  
Vol 287 (6) ◽  
pp. F1171-F1178 ◽  
Author(s):  
Gerald F. DiBona ◽  
Linda L. Sawin
Keyword(s):  
Angiotensin Ii ◽  
Frequency Response ◽  
Renin Angiotensin System ◽  
Tubuloglomerular Feedback ◽  
Renal Vasculature ◽  
Renal Nerve ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
High Sodium ◽  
Sodium Diet

The renal vasculature functions as an efficient low-pass filter of the multiple frequencies contained within renal sympathetic nerve activity. This study examined the effect of angiotensin II on the frequency response of the renal vasculature. Physiological changes in the activity of the endogenous renin-angiotensin system were produced by alterations in dietary sodium intake. The frequency response of the renal vasculature was evaluated using pseudorandom binary sequence renal nerve stimulation, and the role of angiotensin II was evaluated by the administration of the angiotensin II AT1-receptor antagonist losartan. In low-sodium-diet rats with increased renin-angiotensin system activity, losartan steepened the renal vascular frequency response (i.e., greater attenuation); this was not seen in normal- or high-sodium-diet rats with normal or decreased renin-angiotensin system activity. Analysis of the transfer function from arterial pressure to renal blood flow, i.e., dynamic autoregulation, showed that the tubuloglomerular feedback but not the myogenic component was enhanced in low- and normal- but not in high-sodium-diet rats and that this was reversed by losartan administration. Thus physiological increases in endogenous renin-angiotensin activity inhibit the renal vascular frequency response to renal nerve stimulation while selectively enhancing the tubuloglomerular feedback component of dynamic autoregulation of renal blood flow.

Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations

1993 ◽  
Vol 265 (4) ◽  
pp. F477-F486 ◽  
Author(s):  
S. Anderson ◽  
F. F. Jung ◽  
J. R. Ingelfinger
Keyword(s):  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Hydraulic Pressure ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Renal Vasculature ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ace Activity ◽  
Immunohistochemical Studies

Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.

scholarly journals The tissue renin-angiotensin system in human pancreas

1999 ◽  
Vol 161 (2) ◽  
pp. 317-322 ◽  
Author(s):  
M Tahmasebi ◽  
ER Inwang ◽  
GP Vinson ◽  
Keyword(s):  
Islets Of Langerhans ◽  
Cell Function ◽  
In Situ Hybridisation ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Human Pancreas ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Glucagon And Insulin ◽  
Sites Of Action

Evidence exists for the presence of a discrete tissue renin-angiotensin system (RAS) in mouse and rat pancreas that is thought largely to be associated with the vasculature. To investigate this in the human pancreas, and to establish whether the cellular sites of RAS components include the islets of Langerhans, we used immunocytochemistry to localise the expression of angiotensin II (AT1) receptors and (pro)renin, and non-isotopic in situ hybridisation to localise transcription of the (pro)renin gene. Identification of cell types in the islets of Langerhans was achieved using antibodies to glucagon and insulin. The results show the presence of the AT1 receptor and (pro)renin both in the beta cells of the islets of Langerhans, and in endothelial cells of the pancreatic vasculature. Transcription of (pro)renin mRNA, however, was confined to connective tissue surrounding the blood vessels and in reticular fibres within the islets. These findings are similar to those obtained in other tissues, and suggest that renin may be released from its sites of synthesis and taken up by possible cellular sites of action. The results presented here suggest that a tissue RAS may be present in human pancreas and that it may directly affect beta cell function as well as pancreatic blood flow.

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.

Sign in / Sign up

Export Citation Format

Share Document