Hypertension and obesity independently drive hypertrophy and alter mitochondrial metabolism in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has recently emerged as an insidiously and increasingly prevalent heart failure phenotype. HFpEF often occurs in the context of hypertension and obesity and presents with diastolic dysfunction, ventricular hypertrophy, and myocardial fibrosis. Despite growing study of HFpEF, the causal links between early metabolic changes, bioenergetic perturbations, and cardiac structural remodeling remain unclear.

Six months of physical inactivity is insufficient to cause chronic kidney disease in C57BL/6J mice.

Chronic kidney disease (CKD) is a progressive disorder marked by a decline in kidney function. Obesity and sedentary behavior contribute to the development of CKD, though mechanisms by which this occurs are poorly understood. This knowledge gap is worsened by the lack of a reliable murine CKD model that does not rely on injury, toxin, or gene deletion to induce a reduction in kidney function.

Lack of renoprotective effects of targeting the endothelin A receptor and (or) sodium glucose transporter 2 in a mouse model of Type 2 diabetic kidney disease.

Two recent clinical trials, using sodium glucose cotransporter (SGLT2) or endothelin-A receptor (ET-A) blocker, reported the first efficacious treatments in 18 years to slow progression of diabetic kidney disease (DKD). We hypothesized that combined inhibition of SGLT2 and ET-A receptor may confer greater protection against renal injury than either agent alone. Uninephrectomized male db/db mice were randomized to four groups: vehicle, SGLT2 inhibitor (dapagliflozin (dapa), 1 mg/kg/day), ET-A blocker (atrasentan (atra), 5 mg/kg/day), or dual treatment from 10 weeks until 22 weeks of age.

Profiling renal sodium transporters in mice with nephron Ift88 disruption: Association with sex, cysts, and blood pressure.

Loss of nephron primary cilia due to disruption of the Ift88 gene results in sex- and age-specific phenotypes involving renal cystogenesis, blood pressure (BP) and urinary Na excretion. Previous studies demonstrated that male mice undergoing induction of nephron-specific Ift88 gene disruption at 2 months of age developed reduced BP and increased salt-induced natriuresis when pre-cystic (2 months post-induction) and became hypertensive associated with frankly cystic kidneys by 9 months post-induction; in contrast, female Ift88 KO mice manifested no unique phenotype 2 months post-induction and had mildly reduced BP 9 months post-induction. The current study utilized these Ift88 KO mice to investigate associated changes in renal Na transporter and channel protein expression.

Improving access for the vulnerable: a mixed-methods feasibility study of a pop-up model of care in south-eastern Melbourne, Australia.

Access to appropriate health and social care is challenging for vulnerable populations. We used a 'pop-up' delivery model to bring community-based services in contact with communities with poor access to health and social care. Our aim was to examine whether pop-up events improve access to essential health and social support services for selected vulnerable communities and increase collaboration between community-based health and social services.

Sex-Dependent Effects of Nephron Ift88 Disruption on BP, Renal Function, and Cystogenesis.

Background: Primary cilia regulation of renal function and BP in health and disease is incompletely understood. This study investigated the effect of nephron ciliary loss on renal physiology, BP, and ensuing cystogenesis.

Methods: Mice underwent doxycycline (DOX)-inducible nephron-specific knockout (KO) of the gene at 2 months of age using a Cre-LoxP strategy.

Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury.

[Figure: see text].

Renomedullary Interstitial Cell Endothelin A Receptors Regulate BP and Renal Function.

Background: The physiologic role of renomedullary interstitial cells, which are uniquely and abundantly found in the renal inner medulla, is largely unknown. Endothelin A receptors regulate multiple aspects of renomedullary interstitial cell function .

Methods: To assess the effect of targeting renomedullary interstitial cell endothelin A receptors , we generated a mouse knockout model with inducible disruption of renomedullary interstitial cell endothelin A receptors at 3 months of age.

Nephron-Specific Disruption of Polycystin-1 Induces Cyclooxygenase-2-Mediated Blood Pressure Reduction Independent of Cystogenesis.

Background: Hypertension often occurs before renal function deteriorates in autosomal dominant polycystic kidney disease (ADPKD). It is unknown whether the gene product polycystin-1-the predominant causal factor in ADPKD-itself contributes to ADPKD hypertension independent of cystogenesis.

Methods: We induced nephron-specific disruption of the gene in 3-month-old mice and examined them at 4-5 months of age.

Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion.

Background: In vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na transport.

Methods And Results: To assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline-inducible nephron-wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate.

Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion.

The collecting duct is the predominant nephron site of prorenin and prorenin receptor (PRR) expression. We previously demonstrated that the collecting duct PRR regulates epithelial Na channel (ENaC) activity and water transport; however, which cell type is involved remains unclear. Herein, we examined the effects of principal cell (PC) or intercalated cell (IC) PRR deletion on renal Na and water handling.

Aldosterone does not alter endothelin B receptor signaling in the inner medullary collecting duct.

Recent studies suggest that aldosterone-mediated sulfenic acid modification of the endothelin B receptor (ETB) promotes renal injury in an ischemia/reperfusion model through reduced ETB-stimulated nitric oxide production. Similarly, aldosterone inactivation of ETB signaling promotes pulmonary artery hypertension. Consequently, we asked whether aldosterone inhibits collecting duct ETB signaling; this could promote fluid retention since CD ETB exerts natriuretic and diuretic effects.

Collecting duct-specific knockout of nitric oxide synthase 3 impairs water excretion in a sex-dependent manner.

Nitric oxide (NO) inhibits collecting duct (CD) Na and water reabsorption. Mice with CD-specific knockout (KO) of NO synthase 1 (NOS1) have salt-sensitive hypertension. In contrast, the role of NOS3 in CD salt and water reabsorption is unknown.

Collecting Duct Renin Does Not Mediate DOCA-Salt Hypertension or Renal Injury.

Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet.

Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.

The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance.

Possible role for nephron-derived angiotensinogen in angiotensin-II dependent hypertension.

The role of intranephron angiotensinogen (AGT) in blood pressure (BP) regulation is not fully understood. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, whereas proximal tubule-specific deletion of AGT did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet.

Nephron-specific deletion of the prorenin receptor causes a urine concentration defect.

The prorenin receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiological significance of nephron PRR remains unclear, partly due to developmental abnormalities associated with global or renal-specific PRR gene knockout (KO). Therefore, we developed mice with inducible nephron-wide PRR deletion using Pax8-reverse tetracycline transactivator and LC-1 transgenes and loxP flanked PRR alleles such that ablation of PRR occurs in adulthood, after induction with doxycycline.

Lack of an effect of nephron-specific deletion of adenylyl cyclase 3 on renal sodium and water excretion or arterial pressure.

Adenylyl cyclase (AC)-stimulated cAMP plays a key role in modulating transport and channel activity along the nephron. However, the role of individual adenylyl cyclase isoforms in such regulation is largely unknown. Since adenylyl cyclase 3 (AC3) is expressed throughout nephron, we investigated its role in the physiologic regulation of renal Na(+) and water transport.

Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension.

The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO.

Adenylyl cyclase 4 does not regulate collecting duct water and sodium handling.

Abstract Adenylyl cyclase (AC)-stimulated cAMP is a key mediator of collecting duct (CD) Na and water transport. AC isoforms 3, 4, and 6 are expressed in the CD. Our group demonstrated that AC6, but not AC3, is involved in regulating CD Na and water transport.

Lack of an effect of collecting duct-specific deletion of adenylyl cyclase 3 on renal Na+ and water excretion or arterial pressure.

cAMP is a key mediator of connecting tubule and collecting duct (CD) Na(+) and water reabsorption. Studies performed in vitro have suggested that CD adenylyl cyclase (AC)3 partly mediates the actions of vasopressin; however, the physiological role of CD AC3 has not been determined. To assess this, mice were developed with CD-specific disruption of AC3 [CD AC3 knockout (KO)].

Smooth muscle specific disruption of the endothelin-A receptor in mice reduces arterial pressure, and vascular reactivity and affects vascular development.

Aims: The role of vascular smooth muscle endothelin A receptors (ETA) in development and normal physiology remains incompletely understood. To address this, mice were generated with smooth muscle-specific knockout (KO) of ETA.

Main Methods: Mice were homozygous for loxP-flanked exons 6-8 of the EDNRA gene (floxed) or were also hemizygous for a transgene expressing Cre recombinase under control of the smooth muscle-specific SM22 promoter (KO mice).

Myocardial, smooth muscle, nephron, and collecting duct gene targeting reveals the organ sites of endothelin A receptor antagonist fluid retention.

Endothelin-1 binding to endothelin A receptors (ETA) elicits profibrogenic, proinflammatory, and proliferative effects that can promote a wide variety of diseases. Although ETA antagonists are approved for the treatment of pulmonary hypertension, their clinical utility in several other diseases has been limited by fluid retention. ETA blocker-induced fluid retention could be due to inhibition of ETA activation in the heart, vasculature, and/or kidney; consequently, the current study was designed to define which of these sites are involved.

Overexpression of Renin in the collecting duct causes elevated blood pressure.

Background: Renin is synthesized in the collecting duct and is regulated differently than renin in the juxtaglomerular apparatus. However, the physiological relevance of collecting duct renin remains unknown, particularly with regard to its ability to regulate blood pressure.

Methods: We used gene targeting to generate mice with overexpression of renin in the collecting duct.

A possible interaction between systemic and renal angiotensinogen in the control of blood pressure.

Background: Angiotensinogen (AGT) is synthesized in the liver and proximal tubule. AGT overexpression at either site might increase blood pressure (BP). We used transgenic mice with AGT overexpression in proximal tubule (K), liver (L), or both sites (KL) to determine the relative contributions of hepatic- and proximal tubule-derived AGT in modulating BP.