(Pro)renin receptor in the kidney: function and significance.

(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H+-ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

The prorenin receptor and its soluble form contribute to lipid homeostasis.

Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter-driven Cre to delete PRR in the liver [liver PRR knockout (KO) mice]. Hepatic PRR deletion did not change the body weight but increased liver weights. The deletion of PRR in the liver decreased peroxisome proliferator-activated receptor gamma (PPARγ) and triglyceride levels, but liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic low-density lipoprotein receptor (LDLR) and Sortilin 1 (SORT1) proteins than control (CTL) mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic sterol regulatory element-binding protein 2 (SREBP2) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-R) genes. In addition, the plasma levels of sPRR were significantly higher in liver PRR KO mice than in controls. In vitro studies in HepG2 cells demonstrated that sPRR treatment upregulated SREBP2, suggesting that sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PRR, total cleaved and noncleaved sPRR contents, furin, and Site-1 protease (S1P) were elevated in the adipose tissue of liver PRR KO mice, suggesting that adipose tissue could contribute to the circulating pool of sPRR. Overall, this work supports previous works and opens a new area of investigation concerning the function of sPRR in lipid metabolism and adipose tissue-liver cross talk.NEW & NOTEWORTHY Hepatic PRR and its soluble form, sPRR, contribute to triglyceride and cholesterol homeostasis and hepatic inflammation. Deletion of hepatic PRR decreased triglyceride levels through a PRR-PPARγ-dependent mechanism but increased hepatic cholesterol synthesis through sPRR-medicated upregulation of SREBP-2. Our study highlighted a new paradigm of cross talk between the liver and the adipose tissue involving cholesterol and sPRR.

Adipose-Specific PPARα Knockout Mice Have Increased Lipogenesis by PASK-SREBP1 Signaling and a Polarity Shift to Inflammatory Macrophages in White Adipose Tissue.

The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for ß-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK-SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.

Maternal separation-induced increases in vascular stiffness are independent of circulating angiotensinogen levels.

The renin-angiotensin system (RAS) precursor angiotensinogen (AGT) has been implicated in the functional and mechanical alterations of the vascular wall in response to high-fat diet (HFD). Previously, we showed that HFD exacerbates angiotensin II-induced constriction in isolated aortic rings from male rats exposed to maternal separation (MatSep), a model of early-life stress. Thus, the aim of this study was to investigate whether MatSep increases AGT secretion promoting vascular stiffness in rats fed a HFD. Male Wistar-Kyoto MatSep offspring were separated (3 h/day, postnatal days 2-14), and undisturbed littermates were used as controls. At weaning, rats were fed for 17 wk a normal diet (ND) or a HFD, 18% or 60% kcal from fat, respectively. In plasma, there was a main effect of MatSep reducing AGT concentration (P < 0.05) but no effect due to diet. In urine, ND-fed MatSep rats displayed higher AGT concentrations that were further increased by HFD (P < 0.05 vs. control). AGT mRNA abundance and protein expression were increased in adipose tissue from HFD-fed MatSep rats compared with control rats (P < 0.05). No significant differences in liver and kidney AGT levels were found between groups. In addition, MatSep augmented vascular stiffness assessed on freshly isolated aortic rings from ND-fed rats (P < 0.05), yet HFD did not worsen vascular stiffness in either MatSep or control rats. There was no correlation between plasma AGT and vascular stiffness in ND-fed rats; however, this relationship was negative in HFD-fed MatSep rats only (P < 0.05). Therefore, this study shows that MatSep-induced increases in vascular stiffness are independent of diet or plasma AGT.NEW & NOTEWORTHY This study demonstrates that there was no correlation between circulating levels of angiotensinogen (AGT) and the development of vascular stiffness in rats exposed to early-life stress and fed a normal diet. This study also shows that early-life stress-induced hypersensitive vascular contractility to angiotensin II in rats fed a high-fat diet is independent of circulating levels of AGT and occurs without further progression of vascular stiffness. Our data show that early-life stress primes the adipose tissue to secrete AGT in a sex- and species-independent fashion.

Female Mice Exposed to Postnatal Neglect Display Angiotensin II-Dependent Obesity-Induced Hypertension.

Background We have previously reported that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, show exacerbated diet-induced obesity associated with hypertension. The goal of this study was to test whether MSEW promotes angiotensin II-dependent hypertension via activation of the renin-angiotensin system in adipose tissue. Methods and Results MSEW was achieved by daily separations from the dam and weaning at postnatal day 17, while normally reared controls were weaned at postnatal day 21. Female controls and MSEW weanlings were placed on a low-fat diet (LF, 10% kcal from fat) or high-fat diet (HF, 60% kcal from fat) for 20 weeks. MSEW did not change mean arterial pressure in LF-fed mice but increased it in HF-fed mice compared with controls (P<0.05). In MSEW mice fed a HF, angiotensin II concentration in plasma and adipose tissue was elevated compared with controls (P<0.05). In addition, angiotensinogen concentration was increased solely in adipose tissue from MSEW mice (P<0.05), while angiotensin-converting enzyme protein expression and activity were similar between groups. Chronic enalapril treatment (2.5 mg/kg per day, drinking water, 7 days) reduced mean arterial pressure in both groups of mice fed a HF (P<0.05) and abolished the differences due to MSEW. Acute angiotensin II-induced increases in mean arterial pressure (10 µg/kg SC) were attenuated in untreated MSEW HF-fed mice compared to controls (P<0.05); however, this response was similar between groups in enalapril-treated mice. Conclusions The upregulation of angiotensinogen and angiotensin II in adipose tissue could be an important mechanism by which female MSEW mice fed a HF develop hypertension.

An obligatory role for neurotensin in high-fat-diet-induced obesity.

Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice.

OBJECTIVE: Castration of male apolipoprotein E-deficient (apoE-/-) mice reduces angiotensin II (Ang II)-induced abdominal aorta aneurysms (AAAs) to that of female mice. The purpose of this study was to determine whether this reduction is attributable to androgen-mediated regulation of aortic Ang II type 1A receptors (AT1aR). METHODS AND RESULTS: AT1aR mRNA abundance in the AAA-prone region of abdominal aortas was 8-fold greater compared to thoracic aortas of male but not female mice. AT1aR mRNA abundance decreased after castration in abdominal but not thoracic aortas of male mice. Dihydrotestosterone (DHT, 0.16 mg/d) administration to castrated male mice restored AT1aR mRNA abundance in abdominal aortas but had no effect in thoracic aortas. DHT also increased AT1aR mRNA abundance in abdominal aortas from female mice. Castrated male or female apoE-/- mice were administered DHT during infusion of saline or Ang II (1000 ng/kg/min for 28 days). DHT administration did not alter serum cholesterol concentrations, lipoprotein distributions, or atherosclerotic lesion areas in either male or female mice. However, administration of DHT increased AAA incidence in male (27% placebo versus 75% DHT) and female mice (28% placebo versus 64% DHT). CONCLUSIONS: Androgen promotes AT1aR mRNA abundance in abdominal aortas associated with increased Ang II-induced AAAs.