scholarly journals Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

2021 ◽  
Vol 23 (1) ◽  
pp. 302
Author(s):  
Sae Saigo ◽  
Tabito Kino ◽  
Kotaro Uchida ◽  
Takuya Sugawara ◽  
Lin Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Transgenic Mice ◽  
Renin Angiotensin System ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Blood Pressure Elevation ◽  
Multifunctional Protein ◽  
Over Expression ◽  
Direct Renin Inhibitor ◽  
Renal Tubular

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure

2008 ◽  
Vol 294 (2) ◽  
pp. F326-F335 ◽  
Author(s):  
Hiroyuki Ohnishi ◽  
Shinya Mizuno ◽  
Toshikazu Nakamura
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Repair Process ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Stromal Cell Derived Factor ◽  
Renal Tubular

During the progression of acute renal failure (ARF), the renal tubular S3 segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48 h post-renal ischemia, tubular destruction became evident, followed by two-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days postischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase in BMDC in renal tubules. Under the HGF-neutralized state, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1 receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus possible cascades include 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 upregulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 upregulation, and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF.

RENAL TUBULAR RENIN-ANGIOTENSIN SYSTEM AS A MAJOR DETERMINANT OF BLOOD PRESSURE IN LOW RENIN HYPERTENSIVE WOMEN

2004 ◽  
Vol 22 (Suppl. 2) ◽  
pp. S43
Author(s):  
P. Lantelme ◽  
A. Rohrwasser ◽  
M. Vincent ◽  
M. O. Rial ◽  
L. Legedz ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Major Determinant ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Renal Tubular

Abstract MP09: Effect Of Western Diet On Renal Transcriptome Of Hypertensive Mice Overexpressing Human Angiotensin Receptor Type 1

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Harshada Ketkar ◽  
Samantha Tang ◽  
Sudhir Jain
Keyword(s):  
Blood Pressure ◽  
Renin Angiotensin System ◽  
Renal Tissue ◽  
Western Diet ◽  
Rna Seq ◽  
Angiotensin Ii Receptor ◽  
Regular Diet ◽  
Aged Mice ◽  
Specific Regulation ◽  
Renal Tubular

Over-expression of human angiotensin-II receptor type1 (hAT1R) may cause pathological outcomes due to overactivation of renin-angiotensin system. Transgenic (TG) mice containing Hap-I (hypertensive genotype) of human hAT1R gene are more prone to develop metabolic syndrome disorders as compared to TG mice with Hap-II (normotensive genotype). This gene variant associated risk of hypertension together with Western diet and aging may lead to renal disorders. However, mechanisms underlying this process are not well examined. For this purpose, we studied the renal gene expression alterations in aged TG mice containing either Hap-I or Hap-II of hAT1R gene. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (Western diet, WD) for 16 weeks. On a regular diet, aged Hap-I mice presented higher (~9 mmHg) systolic blood pressure with respect to age-matched Hap-II animals. Following administration of Western diet, blood pressure increased in both groups of mice, but to a larger extent in Hap-I animals (~15 mmHg in comparison to ~7 mmHg in Hap-II). Aged Hap-I mice on Western diet showed increased renal fibrosis. RNA-seq data from renal tissue of Hap-I aged mice revealed that WD significantly altered the expression of >400 genes (p-adj. <0.05). Bioinformatics analysis (Qiagen IPA software) identified major alterations in main canonical pathways involved in renal function and oxidative damage. These changes in turn resulted in kidney failure, renal tubular injury, and renal proliferation. In addition, post WD treatment, RNA seq. analysis from Hap-I and Hap-II kidneys also reveals haplotype specific regulation of genes associated with blood pressure regulation and kidney disorders. Overall, these results indicate that Western diet promotes hypertension and fibrosis in the kidneys of aged mice. These alterations are paralleled by perturbation of renal transcriptional profile. Overall, these studies will assist in the identification of novel mechanisms and molecules involved in hypertension and associated kidney pathophysiology.

scholarly journals PGC-1α overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice

2015 ◽  
Vol 35 (3) ◽  
Author(s):  
Qingbin Zhao ◽  
Junfang Zhang ◽  
Huifang Wang
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Elevation ◽  
Over Expression ◽  
Pressure Elevation ◽  
Enos Uncoupling ◽  
Novel Strategy

PGC-1α over expression restores eNOS uncoupling by increasing BH4 levels and Hsp90/eNOS interaction, enhances NO generation, improves endothelium-dependently relaxation and thus lowers blood pressure. Our findings suggest that forced PGC-1α expression may be a novel strategy to prevent and treat hypertension.

Angiotensin II-mediated nondipping during sleep in healthy humans: effects on baroreflex function at subsequent daytime

2020 ◽  
Vol 318 (4) ◽  
pp. R813-R821
Author(s):  
Friedhelm Sayk ◽  
Christoph Twesten ◽  
Isabel Adametz ◽  
Klaas Franzen ◽  
Reinhard Vonthein ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Muscle Sympathetic Nerve Activity ◽  
Renin Angiotensin System ◽  
Blood Pressure Elevation ◽  
Healthy Humans ◽  
Blood Pressure Homeostasis ◽  
Baroreflex Function ◽  
Blood Pressure Dipping ◽  
Drug Challenge

Blood pressure dipping at night is mediated by sleep-inherent, active downregulation of sympathetic vascular tone. Concomitantly, activity of the renin-angiotensin system is reduced, which might contribute to the beneficial effect of baroreflex downward resetting on daytime blood pressure homeostasis. To evaluate whether experimental nondipping mediated by angiotensin II during sleep would alter blood pressure and baroreflex function the next day in healthy humans, angiotensin-II or placebo (saline) was infused for a 7-h period at night, preventing blood pressure dipping in 11 sleeping normotensive individuals (5 males, balanced, crossover design). Baroreflex function was assessed about 1 h upon awakening and stop of infusion via microneurographic recordings of muscle sympathetic nerve activity (MSNA), showing that resting MSNA was significantly increased following angiotensin II nondipping compared with placebo ( P = 0.029), whereas blood pressure and heart rate remained unchanged. Baroreflex sensitivity in response to vasoactive drug challenge was preserved, and neuroendocrine markers of fluid balance and electrolytes did not differ between conditions. Ambulatory blood pressure during subsequent daytime was not altered. Data were compared with analog experiments previously performed within the same subjects during awake daytime (ANCOVA). We conclude that angiotensin-II mediated nocturnal nondipping did not induce blood pressure elevation at subsequent daytime in healthy humans but was linked to increased vasoconstrictive sympathetic activity. This is in contrast to a prolonged increase in blood pressure in corresponding daytime experiments of the same individuals. Evidently, sleep strongly preserves normotensive blood pressure homeostasis in healthy humans.

scholarly journals miR-6869-5p Transported by Plasma Extracellular Vesicles Mediates Renal Tubule Injury and Renin-Angiotensin System Activation in Obesity

2021 ◽  
Vol 8 ◽  
Author(s):  
Huan-Huan Liu ◽  
Xia-Qing Li ◽  
Jin-Feng Liu ◽  
Shuang Cui ◽  
Han Liu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Tubule ◽  
Renin Angiotensin System ◽  
Tubular Damage ◽  
Tubular Injury ◽  
Renal Tubular Damage ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Activation ◽  
Renal Tubular

Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs) in vitro. Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injury in vivo. The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.

Abstract MP31: A20 In Renal Tubular Cells Protects Against Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Xiaohan Lu ◽  
Jiafa Ren ◽  
Robert Griffiths ◽  
Gianna Hammer ◽  
Ting Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Sodium Reabsorption ◽  
Mrna Levels ◽  
Blood Pressure Elevation ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Pressure Elevation ◽  
Tnf Α ◽  
Renal Tubular

The ubiquitin-editing protein A20 suppresses NF-κB signaling, which contributes to hypertension and kidney inflammation. However, whether A20 generated directly in the kidney tubule regulates blood pressure requires elucidation. To examine the role of tubular A20 in hypertension, we bred A20 flox/flox mice with the Pax8-rtTA and Tet-On lines to generate inducible renal epithelial cell A20 knockout mice (A20 iKKO). Mice with all 3 transgenes were used as the A20 iKKO group, while mice lacking the Pax8-rtTA or Tet-On transgene acted as wild-type (WT) controls. Prior to experiments, all mice were given 2mg/ml of doxycycline in the drinking water for 2 weeks to ablate A20 in renal tubular cells. By qPCR, mRNA levels for A20 were selectively reduced by 63% in A20 iKKO kidneys vs WT controls. Baseline blood pressures were similar in the groups. During 3 weeks of chronic angiotensin (Ang) II infusion (500ng/kg/min), A20 iKKO mice exhibited higher mean arterial pressures measured by telemetry compared to WTs (155±2 vs. 143±4 mmHg; p =0.024). As a result, the A20 iKKOs had worse cardiac hypertrophy than the WTs after AngII (7.10±0.17 vs. 6.27±0.16 mg heart/g body weight; p <0.005.). In addition, mRNA levels for TNF-α were markedly increased (1.54±0.21 vs. 1.0±0.1 arbitrary units; p <0.05) in A20 iKKO kidneys compared to WTs, whereas the genes encoding IL-1β and IFNγ were similarly expressed in the groups. In the 3 rd week of AngII, levels of sodium-hydrogen exchanger 3 (NHE3) protein (1.50±0.10 vs. 1.0±0.1; p <0.0005) and NF-κB p50 subunit mRNA (1.30±0.14 vs. 1.0±0.06; p <0.05) were increased in A20 iKKO kidneys compared to WTs. Treating both WTs and A20 iKKOs with the TNF-α inhibitor (R7050, 12mg/body weight) every other day during the 1 st week of AngII infusion yielded similar levels of blood pressure elevation (141.57±4.54 vs. 140.35±5.60 mmHg; p =0.87). These data suggest that tubular A20 limits sodium reabsorption and blood pressure elevation by inhibiting NF-κB/ TNF-dependent NHE3 induction in the kidney.

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