Dataset Information

Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis-Brief Report.

ABSTRACT: Objective- AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system that is sequentially cleaved by renin and ACE (angiotensin-converting enzyme) to produce Ang II (angiotensin II). In this study, we determined how these renin-angiotensin components interact with megalin in kidney to promote atherosclerosis. Approach and Results- AGT, renin, ACE, and megalin were present in the renal proximal convoluted tubules of wild-type mice. Hepatocyte-specific AGT deficiency abolished AGT protein accumulation in proximal tubules and diminished Ang II concentrations in kidney, while renin was increased. Megalin was most abundant in kidney and exclusively present on the apical side of proximal tubules. Inhibition of megalin by antisense oligonucleotides (ASOs) led to ablation of AGT and renin proteins in proximal tubules, while leading to striking increases of urine AGT and renin concentrations, and 70% reduction of renal Ang II concentrations. However, plasma Ang II concentrations were unaffected. To determine whether AGT and megalin interaction contributes to atherosclerosis, we used both male and female low-density lipoprotein receptor-/- mice fed a saturated fat-enriched diet and administered vehicles (PBS or control ASO) or megalin ASO. Inhibition of megalin did not affect plasma cholesterol concentrations, but profoundly reduced atherosclerotic lesion size in both male and female mice. Conclusions- These results reveal a regulatory role of megalin in the intrarenal renin-angiotensin homeostasis and atherogenesis, positing renal Ang II to be an important contributor to atherosclerosis that is mediated through AGT and megalin interactions.

SUBMITTER: Ye F

PROVIDER: S-EPMC6344256 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis-Brief Report.

Ye Feiming F Wang Ya Y Wu Congqing C Howatt Deborah A DA Wu Chia-Hua CH Balakrishnan Anju A Mullick Adam E AE Graham Mark J MJ Danser A H Jan AHJ Wang Jian'an J Daugherty Alan A Lu Hong S HS

Arteriosclerosis, thrombosis, and vascular biology 20190201 2

Objective- AGT (Angiotensinogen) is the unique precursor of the renin-angiotensin system that is sequentially cleaved by renin and ACE (angiotensin-converting enzyme) to produce Ang II (angiotensin II). In this study, we determined how these renin-angiotensin components interact with megalin in kidney to promote atherosclerosis. Approach and Results- AGT, renin, ACE, and megalin were present in the renal proximal convoluted tubules of wild-type mice. Hepatocyte-specific AGT deficiency abolished ...[more]

PMID: 30567480

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Project description:BACKGROUND: Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals. METHODS: Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System. RESULTS: Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (?² = 7.02; p = 0.0081) and another GGCGGAGT (?² = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (?2 = 5.66; p = 0.017) and ATTGAGAC (?² = 5.93; p = 0.015), obesity with GGCGGAGT (?² = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (?² = 6.68; p = 0.010) and GGTGGGAT (?² = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD. CONCLUSION: These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.

Dataset Information

Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis-Brief Report.

Publications

Angiotensinogen and Megalin Interactions Contribute to Atherosclerosis-Brief Report.

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