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Comparative proteomic analysis in microdissected renal vessels of hypertensive and normotensive rats

ABSTRACT: Systemic hypertension has a profound impact on the renal vascular physiology. In order to elucidate the biological pathways and macromolecules deregulated by hypertension renal vessels were obtained by Laser Capture Microdissection (LCM) from Spontaneously Hypertensive Rats (SHR) and age-matched controls (20 weeks). Proteomic analysis was performed aiming to detect early molecular alterations associated with hypertension at the renal vessels before the onset of vascular damage. Proteomic analysis identified 688 proteins, of which 58 were differentially expressed (15 up-regulated and 43 down-regulated in SHR). Many of these proteins are involved in vascular tone regulation by modulating the activity of endothelial Nitric Oxide Synthase (eNOS) (e.g. Xaa-Pro aminopeptidase 1 (XPP1), N(G) N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), Dehydropteridine reductase (DHPR)) or in blood pressure control by regulating the renin-angiotensin system (e.g. Glutamyl aminopeptidase/Aminopeptidase A (AMPE), Aminopeptidase N (AMPN)). Moreover, pathway enrichment analysis revealed that the eNOS activation pathway is deregulated only in SHR. Our study demonstrates that hypertension causes early proteomic changes in the renal vessels of SHR. These changes are relevant to vascular tone regulation and consequently may be involved in the development of vascular damage and hypertensive nephrosclerosis. Therefore, the identified proteins could be considered as therapeutic targets.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Kidney

DISEASE(S): Hypertension

SUBMITTER: Jerome Zoidakis

LAB HEAD: Jerome Zoidakis

PROVIDER: PXD008792 | Pride | 2022-03-03

REPOSITORIES: Pride

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Project description:Background: The vascular wall of small arteries is heavily affected by high blood pressure. However, the underlying mechanisms causing vascular changes are not fully elucidated. Using a novel data-independent acquisition mass spectrometry (DIA-MS) approach, we aimed to determine the proteomic changes in small mesenteric arteries during early-onset high blood pressure in a rat model of hypertension. Methods: Snap frozen small mesenteric and renal arteries from the spontaneous hypertension rat (SHR) model and Wistar Kyoto (WKY) control rats were collected from two time points (6- and 12-weels of age) and analyzed by a label free quantitative DIA-MS workflow. Mesenteric arteries from Wister Hannover rats were included as an additional control to clarify genetic drift caused by selective inbreeding. Results: We identified a total of 3956 consistent proteins in the mesenteric artery wall and found that 286 proteins were significantly regulated in 12-weeks old SHRs compared to WKY controls. Comparing to an in silico matrisome database, we identified 38 extracellular matrix-associated proteins that could distinguish SHRs from WKY controls. Furthermore, when comparing the significantly regulated proteins identified in mesenteric and renal arteries, we identified 18 proteins, including Serpina3l, Igg-2a, ENSRNOG00000049829, Acyp2, Enpp3, Lss, Acaa1a, Basp1, an isoform of Basp1, Flot1, Flot2, Gstt1, Nit1, Ppid, Ikbkap, Poglut3, P4ha2 and Usp15, that were changed in both vascular beds. These proteins were associated with vital cellular processes, such as dyslipidemia, protease inhibition, remodeling and generation of reactive oxygen species. Majority of the identified proteins and pathways were associated with hypertension, and mapping the underlying changes help understanding the pathological processes occurring in the arterial wall during early-onset hypertension. Conclusions: Our data provides an in-depth analysis of the proteomic architecture of the mesenteric and renal artery wall from SHRs and WKY control rats. We identified 18 novel candidate proteins that highlights critical changes in small arteries of the SHR.

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Comparative proteomic analysis in microdissected renal vessels of hypertensive and normotensive rats

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