Angiotensin II mediates downregulation of aquaporin water channels and key renal sodium transporters in response to urinary tract obstruction

2006 ◽  
Vol 291 (5) ◽  
pp. F1021-F1032 ◽  
Author(s):  
Anja M. Jensen ◽  
Chunling Li ◽  
Helle A. Praetorius ◽  
Rikke Nørregaard ◽  
Sebastian Frische ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Obstruction ◽  
Renin Angiotensin System ◽  
Urine Osmolality ◽  
Water Channels ◽  
Sodium Reabsorption ◽  
Sodium Transporters ◽  
Cox 2

The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT1-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 ± 0.4 vs. 1.7 ± 0.3 ml·min−1·kg−1) and partially prevented the reduction in the expression of AQP2 (66 ± 21 vs. 13 ± 2%, n = 7; P < 0.05), NaPi-2 (84 ± 6 vs. 57 ± 10%, n = 7; P < 0.05), and NKCC2 (89 ± 12 vs. 46% ± 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 ± 4 vs. 97 ± 5 μl·min−1·kg−1, n = 7; P < 0.01) and the reduction in sodium reabsorption (433 ± 62 vs. 233 ± 45 μmol·min−1·kg−1, n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.

Altered expression of major renal Na transporters in rats with bilateral ureteral obstruction and release of obstruction

2003 ◽  
Vol 285 (5) ◽  
pp. F889-F901 ◽  
Author(s):  
Chunling Li ◽  
Weidong Wang ◽  
Tae-Hwan Kwon ◽  
Mark A. Knepper ◽  
Søren Nielsen ◽  
...  
Keyword(s):  
Ureteral Obstruction ◽  
Molecular Mechanisms ◽  
Urinary Tract Obstruction ◽  
Urinary Sodium Excretion ◽  
Urinary Sodium ◽  
Altered Expression ◽  
Sodium Transporters ◽  
Type 3

Urinary tract obstruction impairs urinary concentrating capacity and reabsorption of sodium. To clarify the molecular mechanisms of these defects, expression levels of renal sodium transporters were examined in rats with 24-h bilateral ureteral obstruction (BUO) or at day 3 or 14 after release of BUO (BUO-R). BUO resulted in downregulation of type 3 Na+/H+ exchanger (NHE3) to 41 ± 14%, type 2 Na-Pi cotransporter (NaPi-2) to 26 ± 6%, Na-K-ATPase to 67 ± 8%, type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) to 20 ± 7%, and thiazide-sensitive cotransporter (TSC) to 37 ± 9%. Immunocytochemistry confirmed downregulation of NHE3, NaPi-2, Na-K-ATPase, BSC-1, and TSC. Consistent with this downregulation, BUO-R was associated with polyuria, reduced urinary osmolality, and increased urinary sodium and phosphate excretion. BUO-R for 3 days caused a persistant downregulation of NHE3 to 53 ± 10%, NaPi-2 to 57 ± 9%, Na-K-ATPase to 62 ± 8%, BSC-1 to 50 ± 12%, and TSC to 56 ± 16%, which was associated with a marked reduction in the net renal reabsorption of sodium (616 ± 54 vs. 944 ± 24 μmol · min-1 · kg-1; P < 0.05) and phosphate (6.3 ± 0.9 vs. 13.1 ± 0.4 μmol · min-1 · kg-1; P < 0.05) demonstrating a defect in renal sodium and phosphate reabsorption capacity. Moreover, downregulation of Na-K-ATPase and TSC persisted in BUO-R for 14 days, whereas NHE3, NaPi-2, and BSC-1 were normalized to control levels. In conclusion, downregulation of renal Na transporters in rats with BUO and release of BUO are likely to contribute to the associated urinary concentrating defect, increased urinary sodium excretion, and postobstructive polyuria.

Local and Downstream Actions of Proximal Tubule Angiotensin II Signaling on Sodium Transporters in the Mouse Nephron

2021 ◽  
Author(s):  
Jonathan William Nelson ◽  
Alicia A. McDonough ◽  
Zhidan Xiang ◽  
Donna L. Ralph ◽  
Joshua A Robertson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Sodium Reabsorption ◽  
Electrolyte Balance ◽  
Sodium Transporters ◽  
Lower Abundance ◽  
Angiotensin Ii Signaling ◽  
Distinct Cell

The renal nephron consists of a series of distinct cell types which function in concert to maintain fluid and electrolyte balance and blood pressure. The renin angiotensin system (RAS) is central to sodium and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered sodium and volume, impacts solute transport throughout the nephron. We hypothesized that proximal tubule (PT) RAS disruption would not only depress PT sodium transporters, but also impact downstream Na+ transporters. Utilizing a mouse model in which the type 1a angiotensin receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of sodium transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (NHE3, NBCe2 and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated NKCC2, medullary Na,K-ATPase, phosphorylated NCC and claudin 7) versus controls. However, transport activities of NKCC2 and NCC (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on sodium reabsorption in PT at baseline and the associated influence on downstream Na+ transporters, highlighting the ability of the nephron to integrate sodium transport along the nephron to maintain homeostasis.

scholarly journals Expression of cyclooxygenase-2 in orbital fibroadipose connective tissues of Graves’ ophthalmopathy patients

2006 ◽  
Vol 155 (5) ◽  
pp. 681-685 ◽  
Author(s):  
E Berrin Yuksel Konuk ◽  
Onur Konuk ◽  
Muge Misirlioglu ◽  
Adnan Menevse ◽  
Mehmet Unal
Keyword(s):  
Disease Duration ◽  
Clinical Activity ◽  
Connective Tissues ◽  
Positive Correlation ◽  
Graves Ophthalmopathy ◽  
Compressive Neuropathy ◽  
The Mean ◽  
Cox 2

Objective: The aim of this study is to evaluate the expression of cycloocygenase-2 (COX-2) in orbital fibroadipose connective tissue in Graves’ ophthalmopathy (GO) patients, and investigate the associations between COX-2 expression and GO characteristics. Methods: The orbital fibroadipose connective tissues of 23 cases demonstrating moderate or severe GO, and eight control subjects without any history of thyroid or autoimmune disease were analyzed for COX-2 mRNA expression. Real-time relative quantitative PCR was performed to assess transcripts of COX-2 using the LightCycler. The disease activity was evaluated by the clinical activity score (CAS). The clinical features of GO were evaluated by total eye score (TES) and the cases were divided into two groups; type 1 cases included higher degrees of proptosis with orbital fat volume increase, and type 2 cases included cases with compressive neuropathy and limited extraocular muscle functions. Results: The mean ± s.d. disease duration was 5.7 ± 7.1 years. The mean ± s.d. CAS and TES of cases were 1.60 ± 1.04 and 7.5 ± 1.8 respectively. The mean ± s.d. expression of COX-2 was 0.023 ± 0.013 and 0.010 ± 0.002 in GO cases and controls (P = 0.008), and 0.015 ± 0.073 and 0.029 ± 0.135 in type 1 and type 2 cases respectively (P = 0.007). COX-2 expression showed a statistically significant positive correlation with TES (r = 0.634, P = 0.001), and a negative correlation with the disease duration (r = −0.621, P = 0.002). Conclusions: COX-2 is expressed at higher levels in orbital fibroadipose tissues of GO cases. This showed a positive correlation with increasing severity of orbital disease suggesting possible relation with COX-2 expression and orbital inflammation in GO.

Angiotensin II type 2 receptor (AT2R) in renal and cardiovascular disease

2016 ◽  
Vol 130 (15) ◽  
pp. 1307-1326 ◽  
Author(s):  
Bryna S.M. Chow ◽  
Terri J. Allen
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Cellular Growth ◽  
Receptor Subtype ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Biological Responses

Angiotensin II (Ang II) is well-considered to be the principal effector of the renin–angiotensin system (RAS), which binds with strong affinity to the angiotensin II type 1 (AT1R) and type 2 (AT2R) receptor subtype. However, activation of both receptors is likely to stimulate different signalling mechanisms/pathways and produce distinct biological responses. The haemodynamic and non-haemodynamic effects of Ang II, including its ability to regulate blood pressure, maintain water–electrolyte balance and promote vasoconstriction and cellular growth are well-documented to be mediated primarily by the AT1R. However, its biological and functional effects mediated through the AT2R subtype are still poorly understood. Recent studies have emphasized that activation of the AT2R regulates tissue and organ development and provides in certain context a potential counter-regulatory mechanism against AT1R-mediated actions. Thus, this review will focus on providing insights into the biological role of the AT2R, in particular its actions within the renal and cardiovascular system.

Improvement of insulin sensitivity by antagonism of the renin-angiotensin system

2007 ◽  
Vol 293 (3) ◽  
pp. R974-R980 ◽  
Author(s):  
Erik J. Henriksen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Transport ◽  
Renin Angiotensin System ◽  
Whole Body ◽  
Ang Ii ◽  
Angiotensin System ◽  
Skeletal Muscle Insulin Resistance

The reduced capacity of insulin to stimulate glucose transport into skeletal muscle, termed insulin resistance, is a primary defect leading to the development of prediabetes and overt type 2 diabetes. Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) produced from this system can act on ANG II type 1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of reactive oxygen species (ROS). Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole body and skeletal muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. Collectively, these findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with prediabetes and type 2 diabetes.

scholarly journals Urinary tract obstruction induces time‐dependent COX‐2 induction and downregulation of AQP2

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Rikke Norregaard ◽  
Tina Madsen ◽  
Boye L. Jensen ◽  
Søren Nielsen ◽  
Jørgen Frøkiær
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Obstruction ◽  
Time Dependent ◽  
Cox 2

scholarly journals Pathological Feature and Immunoprofile of Cystitis Glandularis Accompanied with Upper Urinary Tract Obstruction

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Aihua Li ◽  
Jun Zhou ◽  
Honghai Lu ◽  
Xiaoming Zuo ◽  
Sikuan Liu ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Obstruction ◽  
Upper Urinary Tract ◽  
Pathological Feature ◽  
Immunohistochemical Expression ◽  
Cystitis Glandularis ◽  
Significant Difference ◽  
Cox 2 ◽  
The Difference ◽  
Upper Urinary Tract Obstruction

Objective. To explore the pathological feature and immunoprofile of immunoprofile accompanied with upper urinary tract obstruction and the immunoprofile in various types of glandular cystitis.Methods. Pathological sections from 31 cases of cystitis glandularis with upper urinary tract obstruction and 34 cases of cystitis glandularis without upper urinary tract obstruction were observed as pathological feature on microscopy. Meanwhile, an immunohistochemical analysis was employed to determine the expression of p53, Ki67, p21, MMP-9, MUC1, MUC2, and COX-2.Results. In the two groups, main pathological type was transitional epithelial, followed by intestinal epithelial; other types were a few, and the difference between the two groups was not significant. All immunohistochemical expressions of p53, Ki67, p21, MMP-9, MUC1, MUC2, and COX-2 were positive in varying degrees, and there was no significant difference between the groups. Transitional epithelial type was compared with mixed type; the difference of COX-2 was significant,P<0.05. The differences of immunohistochemical expression among other different pathologic types were not significant.Conclusions. It is suggested that glandular cystitis accompanied with upper urinary tract obstruction shares the same pathological feature and immunoprofile as that without upper urinary tract obstruction. No significant differences of immunohistochemical expression in tissue are in cystitis glandularis with different pathological types.

scholarly journals Autophagy in diabetic nephropathy

2014 ◽  
Vol 224 (1) ◽  
pp. R15-R30 ◽  
Author(s):  
Yan Ding ◽  
Mary E Choi
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Renin Angiotensin System ◽  
Human Kidney ◽  
Nutrient Sensing ◽  
Signal Pathways ◽  
End Stage

Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide, and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Increasing prevalence of diabetes has made the need for effective treatment of DN critical and thereby identifying new therapeutic targets to improve clinical management. Autophagy is a highly conserved ‘self-eating’ pathway by which cells degrade and recycle macromolecules and organelles. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Impairment of autophagy is implicated in the pathogenesis of DN. Emerging body of evidence suggests that targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. In this review, we examine current advances in our understanding of the roles of autophagy in diabetic kidney injury, focusing on studies in renal cells in culture, human kidney tissues, and experimental animal models of diabetes. We discuss the major nutrient-sensing signal pathways and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of advanced glycation end-products, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin–angiotensin system, which modulate autophagic activity and contribute to the development of DN. We also highlight recent studies of autophagy and transforming growth factor-β in renal fibrosis, the final common response to injury that ultimately leads to end-stage kidney failure in both type 1 and type 2 diabetes. These findings suggest the possibility that autophagy can be a therapeutic target against DN.

scholarly journals Is angiotensin-(3–4) (Val-Tyr), the shortest angiotensin II-derived peptide, opening new vistas on the renin–angiotensin system?

2017 ◽  
Vol 18 (1) ◽  
pp. 147032031668933 ◽  
Author(s):  
Juliana Dias ◽  
Flavia Axelband ◽  
Lucienne S. Lara ◽  
Humberto Muzi-Filho ◽  
Adalberto Vieyra
Keyword(s):  
Renin Angiotensin System ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Ang Ii ◽  
Proximal Tubule Cells ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Kinase Pathway

Angiotensin-(3−4) (Ang-(3−4) or Val-Tyr) is the shorter angiotensin (Ang) II-derived peptide, formed through successive hydrolysis that culminates with the release of Val-Tyr as a dipeptide. It is formed both in plasma and in kidney from Ang II and Ang III, and can be considered a component of the systemic and organ-based renin–angiotensin system. It is potently antihypertensive in humans and rats, and its concerted actions on proximal tubule cells culminate in the inhibition of fluid reabsorption, hyperosmotic urinary excretion of Na+. At the renal cell signaling level, Ang-(3−4) counteracts Ang II-type 1 receptor-mediated responses by acting as an allosteric enhancer in Ang II-type 2 receptor populations that target adenosine triphosphate-dependent Ca2+ and Na+ transporters through a cyclic adenosine monophosphate-activated protein kinase pathway.

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