scholarly journals Striatin heterozygous mice are more sensitive to aldosterone-induced injury

2020 ◽  
Vol 245 (3) ◽  
pp. 439-450
Author(s):  
Amanda E Garza ◽  
Elijah Trefts ◽  
Isis A Katayama Rangel ◽  
Danielle Brooks ◽  
Rene Baudrand ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Epithelial Cells ◽  
Active Treatment ◽  
Mineralocorticoid Receptor ◽  
Renal Damage ◽  
Kidney Tissue ◽  
Macrophage Infiltration ◽  
Male Mice ◽  
Wild Type ◽  
Second Messenger Signaling

Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

Hypotension in NKCC1 null mice: role of the kidneys

2006 ◽  
Vol 290 (2) ◽  
pp. F409-F416 ◽  
Author(s):  
Susan M. Wall ◽  
Mark A. Knepper ◽  
Kathryn A. Hassell ◽  
Michael P. Fischer ◽  
Adetola Shodeinde ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Free Water ◽  
Plasma Renin ◽  
Wild Type ◽  
Deficient Diet ◽  
Water Excretion ◽  
Α Subunit ◽  
Serum Aldosterone ◽  
Transporter Expression

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 ( −/−) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 ( +/+) and NKCC1 ( −/−) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 ( −/−) than NKCC1 ( +/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the α-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.

Abstract 358: Excess Cardio-renal Damage in Aldosterone-producing Adenoma Patients With Somatic Mutations in the KCNJ5 Gene

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Gian Paolo Rossi ◽  
Teresa M Seccia ◽  
Claudio Letizia ◽  
Maria Verena Cicala ◽  
Laura Zinnamosca ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Damage ◽  
Somatic Mutations ◽  
Left Ventricular ◽  
K Channel ◽  
Wild Type ◽  
Antihypertensive Medications ◽  
Plasma Aldosterone Concentration ◽  
Lower Egfr ◽  
Aldosterone Producing Adenoma

Aldosterone exerts detrimental cardiovascular (CV) effects, and aldosterone producing adenoma (APA) patients carrying somatic mutations in the KCNJ5 K+ channel (mutAPA) have higher plasma aldosterone concentration (PAC) than those wild-type (wtAPA). We therefore investigated whether mutAPA patients develop a more prominent CV and renal damage than wtAPA patients. From 250 consecutive PA patients, we identified 170 who had a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them 106 with KCNJ5 sequencing information and long-term follow-up data could be compared for echocardiographic changes and eGFR (by CKD-EPI equation) according to presence (mutAPA, 18.8%) or absence (wtAPA, 81.2%) of the KCNJ5 mutations. At baseline the mutAPA had lower eGFR (75±29 ml/min vs 84±20, p<0.05), and higher left ventricular mass index (LVMI, 61.9±21.4 mg/h2.7vs 49.5±11.3, p=0.001), PAC (48.9 [37.4-77.1] ng/dl vs 37.0 [24.9-48.5]), <0.0001), aldosterone-renin-ratio (ARR, 173.5 [92.2-229.6] ng/dl/ng/ml/h vs 144.3 [69.9-252.1], <0.0001), than the wtAPA patients. They were similar for blood pressure (BP) and need for antihypertensive medications. After adrenalectomy BP, PAC, ARR, and LVMI normalized in all groups, with no difference between mutAPA vs wtAPA. Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular and renal damage, likely because of the higher PAC. However, the presence of these mutations did not compromise the chances of being cured from the hyperaldosteronism and the high blood pressure, or the regression of LVMI after adrenalectomy.

scholarly journals Gender- and Age-dependent Changes in Kidney Androgen Protein mRNA Expression in a Knockout Mouse Model for Nephrolithiasis

2002 ◽  
Vol 50 (12) ◽  
pp. 1663-1669 ◽  
Author(s):  
Eleni G. Tzortzaki ◽  
Dayna Glass ◽  
Min Yang ◽  
Andrew P. Evan ◽  
Sharon B. Bledsoe ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Kidney Tissue ◽  
Mouse Kidney ◽  
Male Mice ◽  
Wild Type ◽  
Rt Pcr ◽  
Cytoplasmic Staining ◽  
Female Mice ◽  
Age Dependent ◽  
Wild Type Male

Kidney androgen-regulated protein (Kap) is the most abundant protein in the mouse kidney, but its function is unknown. We previously observed a significant decrease in Kap mRNA expression in whole kidney tissue from male mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. The disease phenotype is more severe in male mice and is age-dependent. To identify the cellular basis for differential Kap expression, we used in situ hybridization (ISH) and reverse transcription-polymerase chain reaction ISH (RT-PCR ISH) to identify the cell types expressing this mRNA in paraffin-embedded kidney sections. In 1-month-old wild-type male mice, Kap was detected primarily in S3 proximal tubule segments, but expression was very low in female mice. In 1-month-old APRT-deficient male mice, Kap expression was decreased significantly and was undetectable in female mice. Kap mRNA was not detected in 3- or 6-month-old mice using our standard ISH protocol, but we observed intense cytoplasmic staining in S3 proximal tubules in wild-type male mice of these age groups using an improved RT-PCR ISH procedure. Our studies demonstrate age-, gender-, and APRT genotype-dependent changes in Kap mRNA expression in mouse kidney. Kap expression is under multihormonal control, and hormonal changes in DHA-induced nephrolithiasis may account for the decreased Kap expression in APRT-deficient mice.

scholarly journals Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3416-3425 ◽  
Author(s):  
Laura A. Bienvenu ◽  
James Morgan ◽  
Amanda J. Rickard ◽  
Greg H. Tesch ◽  
Greg A. Cranston ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Plasma Aldosterone ◽  
Mrna Levels ◽  
Wild Type ◽  
And Oxidative Stress

Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type l-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both l-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by l-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both l-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNFα mRNA expression was greater in wild-type l-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, l-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 ± 0.215 vs. 1 ± 0.073) but not mac-MRKO mice (1.403 ± 0.150 vs. 1.286 ± 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated.

scholarly journals Soluble syndecan-1 and glycosaminoglycans in preeclamptic and normotensive pregnancies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
H. Hassani Lahsinoui ◽  
F. Amraoui ◽  
L. J. A. Spijkers ◽  
G. J. M. Veenboer ◽  
S. L. M. Peters ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heparan Sulphate ◽  
Activated Partial Thromboplastin Time ◽  
Male Mice ◽  
Wild Type ◽  
Dermatan Sulphate ◽  
Keratan Sulphate ◽  
Blood Pressure Elevation ◽  
Wild Type Male ◽  
Deficient Mice

AbstractPreeclampsia, an important cause of maternal and fetal morbidity and mortality, is associated with increased sFLT1 levels and with structural and functional damage to the glycocalyx contributing to endothelial dysfunction. We investigated glycocalyx components in relation to preeclampsia in human samples. While soluble syndecan-1 and heparan sulphate were similar in plasma of preeclamptic and normotensive pregnant women, dermatan sulphate was increased and keratan sulphate decreased in preeclamptic women. Dermatan sulphate was correlated with soluble syndecan-1, and inversely correlated with blood pressure and activated partial thromboplastin time. To determine if syndecan-1 was a prerequisite for the sFlt1 induced increase in blood pressure in mice we studied the effect of sFlt1 on blood pressure and vascular contractile responses in syndecan-1 deficient and wild type male mice. The classical sFlt1 induced rise in blood pressure was absent in syndecan-1 deficient mice indicating that syndecan-1 is a prerequisite for sFlt1 induced increase in blood pressure central to preeclampsia. The results show that an interplay between syndecan-1 and dermatan sulphate contributes to sFlt1 induced blood pressure elevation in pre-eclampsia.

scholarly journals The effect of spironolactone on cardiac and renal fibrosis following myocardial infarction in established hypertension in the transgenic Cyp1a1Ren2 rat

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260554
Author(s):  
C. J. Leader ◽  
G. T. Wilkins ◽  
R. J. Walker
Keyword(s):  
Myocardial Infarction ◽  
Mineralocorticoid Receptor ◽  
Cardiac Fibrosis ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Macrophage Infiltration ◽  
Receptor Blockade ◽  
Receptor Antagonism ◽  
Mineralocorticoid Receptor Antagonism ◽  
Mineralocorticoid Receptor Blockade

Aims The renin-angiotensin-aldosterone axis plays a key role in mediating cardiac and kidney injury. Mineralocorticoid receptor antagonism has beneficial effects on cardiac dysfunction, but effects are less well quantified in the cardiorenal syndrome. This study investigated cardiac and kidney pathophysiology following permanent surgical ligation to induce myocardial infarction (MI) in hypertensive animals with or without mineralocorticoid receptor antagonism. Methods Hypertension was induced in adult male Cyp1a1Ren2 rats. Hypertensive animals underwent MI surgery (n = 6), and were then treated daily with spironolactone for 28 days with serial systolic blood pressure measurements, echocardiograms and collection of urine and serum biochemical data. They were compared to hypertensive animals (n = 4), hypertensive animals treated with spironolactone (n = 4), and hypertensive plus MI without spironolactone (n = 6). Cardiac and kidney tissue was examined for histological and immunohistochemical analysis. Results MI superimposed on hypertension resulted in an increase in interstitial cardiac fibrosis (p<0.001), renal cortical interstitial fibrosis (p<0.01) and glomerulosclerosis (p<0.01). Increased fibrosis was accompanied by myofibroblast and macrophage infiltration in the heart and the kidney. Spironolactone post-MI, diminished the progressive fibrosis (p<0.001) and inflammation (myofibroblasts (p<0.05); macrophages (p<0.01)) in both the heart and the kidney, despite persistently elevated SBP (182±19 mmHg). Despite the reduction in inflammation and fibrosis, spironolactone did not modify ejection fraction, proteinuria, or renal function when compared to untreated animals post MI. Conclusion This model of progressive cardiorenal dysfunction more closely replicates the clinical setting. Mineralocorticoid receptor blockade at a clinically relevant dose, blunted progression of cardiac and kidney fibrosis with reduction in cardiac and kidney inflammatory myofibroblast and macrophage infiltration. Further studies are underway to investigate the combined actions of angiotensin blockade with mineralocorticoid receptor blockade.

Abstract 089: Dopamine D 2 Receptor is Associated with Inverse Salt Sensitivity

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Peng Xu ◽  
John J Gildea ◽  
Pedro A Jose ◽  
Robert M Carey ◽  
Robin A Felder
Keyword(s):  
Blood Pressure ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Salt Sensitivity ◽  
T Test ◽  
Receptor Expression ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Tissue Slices ◽  
Type D

Our previous studies of salt sensitivity of blood pressure have demonstrated that approximately 11% of study participants have a paradoxical increase in blood pressure (> or = to 7-mm Hg) on a low NaCl diet (defined as inverse salt sensitivity (ISS)). However the mechanisms responsible for this effect are not known. We demonstrated that single nucleotide polymorphisms (SNPs) in the dopamine type 2 receptor (D 2 R) (RS6276 and 6267) are highly associated with ISS ( P values of 1.0х10 –2 and 3.8х10 –2 with odds ratios of 0.32 and 0.48 in unadjusted regression models, respectively). The C allele at both sites confers protection. The D 2 R is strongly expressed throughout the cytoplasm of proximal tubule cells in human kidney tissue slices. We also cultured RPTC from the urine from 4 salt resistant (SR) and 3 ISS participants enrolled in our clinical salt sensitivity studies. We hypothesize that D 2 R containing SNPs have altered receptor expression, and altered signaling compared to wild type controls. ISS participants were homozygous variant for the two D 2 R alleles and showed more D 2 R expression than SR RPTC heterozygous variant (HV) for the two alleles (ISS: 1.166±0.059 n=3 vs SR: 0.969±0.024 n=4, P<0.05, t-test). D 2 R expression was increased when the ISS cells were stimulated by a non-selective D 2 R agonist bromocriptine to a greater extent in the D 2 R SNP cell lines (ISS: VEH 1.166±0.059, vs bromocriptine 1.474 ± 0.040, n=3, P<0.05, t-test). Using the ROS reagent assay, dihydroethidium, there was found to be more ROS products in ISS cells than SR cells when stimulated under low salt (ISS: 1.145 ± 0.053, n=3 vs SR: 0.722 ± 0.101, n=4, P<0.05, t-test). We used a highly selective D 2 R agonist (sumanirole) to stimulate wild-type and SNPed cells, and the results demonstrated no effect in the cells with wild type D 2 R but an increase in ROS in cells heterozygous for the D 2 R SNPs (SNP: VEH 38,364±1,266, sumanirole 50,926 ± 3,310, VS WT: VEH 34,562±1,831 sumanirole 34,435 ± 1,614 RFU n=12, P<0.05, t-test) consistent with the higher expression of D 2 R found in ISS urine cells. We hypothesize that SNPs in the D 2 R lead to increased reactive oxygen species which has previously been associated with renal fibrosis and hypertension.

scholarly journals Glomerular Hypertrophy and Alterations in Renin-Angiotensin System Activation Are Associated with Diminished Systemic Blood Pressure in Aging Mice with Sickle Cell Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2362-2362 ◽  
Author(s):  
Pamela L. Brito ◽  
Erica M.F. Gotardo ◽  
Hanan Chweih ◽  
Wilson A. Ferreira ◽  
Flavia C. Leonardo ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Young Adult ◽  
Sickle Cell ◽  
Renal Damage ◽  
Renin Angiotensin System ◽  
Systemic Blood Pressure ◽  
Glomerular Hypertrophy ◽  
Male Mice ◽  
Systemic Blood ◽  
Angiotensin System

Abstract Sickle cell nephropathy is a major and severe clinical complication of sickle cell anemia (SCA). The hypoxic microenvironment of the renal medulla leads to hyperosmolarity and acidosis, which favors deoxygenated hemoglobin S (HbS) polymerization and subsequent sickling of erythrocytes, promoting vaso-occlusive processes in the organ. Renal ischemia and glomerular blood flow can modulate angiotensin II (AngII) production, a vasoconstrictor hormone derivative of the Renin-Angiotensin System (RAS), which regulates blood pressure (BP), among other functions. Considering the elevated blood volume and cardiac output in individuals with SCA, an increase in BP might be expected; however SCA patients often present lower PB (Pikilidou et al., J Clin Hypertens., 2015), which modifies with aging. Reduced plasma AngII in male mice with SCA has been reported previously (Dos Santos et al., Life Sci., 2014), thus we aimed to investigate changes in PB and RAS, in association with aging and renal alterations in an animal model of SCA. Male chimeric mice without SCA (QCON) and male chimeric mice with SCA (QSCA) were generated by the irradiation of 8-week old C57BL6 mice followed by bone marrow cell transplantation from C57BL6 or transgenic Berkeley SCA mice, respectively. As circulating and tissue RAS are markedly affected by estrogens, we used only male mice for all protocols. Animals were subdivided into young adults (5 months of age) and adults (8 - 9 months of age). After confirming the phenotype of the transplanted SCA mice, BP was measured by a noninvasive method (NBP - AdInstruments) and animals were sacrificed at the age of 5/9 months for biological material collection. Plasma AngII and Angiotensin Convertor Enzyme (ACE) were quantified by ELISA. For histological analysis of the kidneys, organ specimens were fixed and embedded in historesin, sectioned and stained with hematoxylin and eosin. Renal AngI/II was quantitated by Western Blot from snap-frozen kidneys. The mean BPs of QSCA at 5 and 8 months old were significantly lower (87.9 ± 1.9 mmHg, n=12; and 94.31 ± 4.4 mmHg, n=2; respectively) than those of QCON of the same age (108.9 ± 5 mmHg, n=10; and 110.6 ± 2.2 mmHg, n=9; respectively), indicating that this model mimics the pathological changes in the blood flow that occur in SCA patients. Given the close relationship between AngII and PB regulation, we investigated whether the RAS is altered in QSCA mice at these ages. Both young adult and adult male QSCA mice presented lower plasma AngII concentrations (young adult, 24.18 ± 3 pg/ml, n= 11; adult, 16.44 ± 2 pg/ml, n=4), compared to QCON animals (young adult, 38.77 ±9, n= 10; adult, 35.52 ± 5.3 pg/ml, n=10, P<0.05, compared to QSCA); however no significant correlation between reduced BP and reduced plasma AngII was observed. AngII is produced by the cleavage of AngI by ACE; plasma ACE concentrations were also reduced in young adult QSCA mice (12.5 ± 1.8 pg/ml, n=11), compared to young adult QCON mice (21.9 ± 4.9 pg/ml, n=9). Moreover, reduced ACE concentrations in young adult/adult QSCA correlated with plasma levels of AngII (rs=0.785, P<0.001, n=15). Findings imply that AngII generation could be compromised in the organs of SCA mice; indeed, intra-renal AngI/II protein expression analysis showed that adult QSCA mice presented a significantly reduced expression of renal AngI/II (0.71 ± 0.2 AU, normalized to β-actin) compared to adult QCON mice (1.6 ± 0.2 AU), suggesting a low production of this hormone at advanced age in SCA. Glomerular hypertrophy increases in cardiovascular and renal disease models, including in hypertension and SCA. Quantitative morphometric analyses showed expansion of the glomerular-capillary tuff area of QSCA mice, which increased with age (young-adult: 372.2 ± 12.8 µm2; adult: 412.9 ±12.1 µm2, n=3), compared to young-adult and adult QCON mice (324.1 ± 10.8 µm2; 332.8 ± 12.4 µm2, n=3, p<0.001). As such, glomerular hypertrophy may reflect hyperfiltration and renal damage in the SCA mice, which apparently augments with age. Subsequent alterations in glomerular pressure may incur adaptive responses in the RAS, in turn diminishing ACE and AngII production, in association with alterations in systemic blood pressure. An understanding of the RAS in SCA may improve our understanding of renal damage and its systemic consequences in SCA and will be important for determining how ACE inhibitor and AngII receptor blockers drugs may be best utilized in these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hypertension induces glomerulosclerosis in phospholipase C-ε1 deficiency

2020 ◽  
Vol 318 (5) ◽  
pp. F1177-F1187 ◽  
Author(s):  
Douglas K. Atchison ◽  
Christopher L. O’Connor ◽  
Rajasree Menon ◽  
Edgar A. Otto ◽  
Santhi K. Ganesh ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Phospholipase C ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Ang Ii ◽  
Loss Of Function ◽  
Wild Type ◽  
Podocyte Loss ◽  
Deficient Mice ◽  
Glomerular Damage

Loss-of-function mutations in phospholipase C-ε1 (PLCE1) have been detected in patients with nephrotic syndrome, but other family members with the same mutation were asymptomatic, suggesting additional stressor are required to cause the full phenotype. Consistent with these observations, we determined that global Plce1-deficient mice have histologically normal glomeruli and no albuminuria at baseline. Angiotensin II (ANG II) is known to induce glomerular damage in genetically susceptible individuals. Therefore, we tested whether ANG II enhances glomerular damage in Plce1-deficient mice. ANG II increased blood pressure equally in Plce1-deficient and wild-type littermates. Additionally, it led to 20-fold increased albuminuria and significantly more sclerotic glomeruli in Plce1-deficient mice compared with wild-type littermates. Furthermore, Plce1-deficient mice demonstrated diffuse mesangial expansion, podocyte loss, and focal podocyte foot process effacement. To determine whether these effects are mediated by hypertension and hyperfiltration, rather than directly through ANG II, we raised blood pressure to a similar level using DOCA + salt + uninephrectomy and norepinephrine. This caused a fivefold increase in albuminuria in Plce1-deficient mice and a significant increase in the number of sclerotic glomeruli. Consistent with previous findings in mice, we detected strong PLCE1 transcript expression in podocytes using single cell sequencing of human kidney tissue. In hemagglutinin-tagged Plce1 transgenic mice, Plce1 was detected in podocytes and also in glomerular arterioles using immunohistochemistry. Our data demonstrate that Plce1 deficiency in mice predisposes to glomerular damage secondary to hypertensive insults.

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