Identification of a common molecular pathway in hypertensive renal damage

Skogstrand, Trude; Leh, Sabine; McClure, John; Dashti, Mohammed; Iversen, Bjarne M.; Graham, Delyth; McBride, Martin W.; Hultström, Michael

doi:10.1097/hjh.0000000000000395

Cited by 7 publications

(14 citation statements)

References 38 publications

(47 reference statements)

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“…Transgelin was more than 3 times abundant in 2K1C tubuli compared with sham. The same was seen in fresh-frozen cortex and in a previous whole cortex microarray study of 3 hypertensive rat models [31]. Transgelin has been shown to mediate transforming growth factor beta (TGF-β)-induced tissue fibrosis in lung epithelial cells [32], and was upregulated in TGF-β treated renal tubular cells in vitro [33].…”

Section: Discussionsupporting

confidence: 53%

Proteomic Analysis of Minimally Damaged Renal Tubular Tissue from Two-Kidney-One-Clip Hypertensive Rats Demonstrates Extensive Changes Compared to Tissue from Controls

Finne

Marti

Leh

et al. 2016

Nephron

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Background: Tubular atrophy and interstitial fibrosis mark the final stage in most forms of progressive kidney diseases. Little is known regarding changes in the tubular proteome. In this study, we investigated changes in the tubular proteome of normal or minimally damaged tubular tissue in the non-clipped kidney from rats with two-kidney one-clip (2K1C) hypertension. Methods: Formalin-fixed paraffin-embedded kidney sections from four 2K1C rats with hypertensive kidney damage and 6 sham rats were used. Tubulointerstitial tissue without discernable interstitial expansion or pronounced tubular alterations was microdissected and this was assumed to represent an early stage of chronic tubular damage in 2K1C. Samples were analyzed by mass spectrometry and relative protein abundances were compared between 2K1C and sham. Results: A total of 1,160 proteins were identified with at least 2 unique peptides, allowing for relative quantitation between samples. Among these, 151 proteins were more abundant, and 192 proteins were less abundant in 2K1C compared with sham. Transgelin, vimentin and creatine kinase B-type were among the proteins that were most increased in 2K1C. Ingenuity Pathway Analysis showed increased abundance of proteins related to Rho signaling and protein turnover (eIF2 signaling and protein ubiquitination), and decreased abundance of proteins related to fatty acid β-oxidation. Conclusion: Tubular tissue from normal or minimally damaged hypertensive kidney damage demonstrate extensive proteomic changes with upregulation of pathways associated with progressive kidney damage, such as Rho signaling and protein turnover. Thus, proteomics presents itself to be a promising tool for the discovery of early damage markers from not yet morphologically visible tubular damage.

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Section: Discussionsupporting

confidence: 53%

Proteomic Analysis of Minimally Damaged Renal Tubular Tissue from Two-Kidney-One-Clip Hypertensive Rats Demonstrates Extensive Changes Compared to Tissue from Controls

Finne

Marti

Leh

et al. 2016

Nephron

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“…Finally, adventitial expression of Annexin-A2 is interesting as we have previously shown that fibrosis in the 2K1C can first be detected in this specific localization of Annexin-A2 (46). This is consistent with earlier findings that NFAT activation regulates ADAMTS-1 in vascular remodeling (38) and with our previous data showing ADAMTS-1 upregulation in chronic hypertensive damage (45). Surprisingly, although mRNA-independent elevation of NFAT5 protein level following AT1R activation correlates with Annexin-A2 binding, AT1R inhibition by losartan caused increased levels of both NFAT5 mRNA and protein.…”

Section: F107supporting

confidence: 90%

“…Gene expression data from 10-wk-old 2K1C rats after 4 wk of hypertension and age-matched controls were downloaded from Array Express (accession no. E-MTAB-1449, https://www.ebi.ac.uk/arrayexpress/) (45). The data were reanalyzed from bead-level using the beadarray package and R/Bioconductor.…”

Section: Methodsmentioning

confidence: 99%

“…Hypertension-induced structural kidney damage is a late development and normally progresses from early vascular engagement (46) to glomerular damage when vascular damage leads to impaired autoregulation (43) or to tubular atrophy when vascular hypertrophy impinges on glomerular filtration (29,45). The two-kidney, one-clip (2K1C) model of renal hypertension (14) is a common experimental model of hypertension in rats (17).…”

Section: Introductionmentioning

confidence: 99%

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NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

Fähling

Paliege

Jönsson

et al. 2019

American Journal of Physiology-Renal Physiology

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The aim was to identify new targets that regulate gene expression at the posttranscriptional level in angiotensin II (ANGII)-mediated hypertension. Heparin affinity chromatography was used to enrich nucleic acid-binding proteins from kidneys of two-kidney, one-clip (2K1C) hypertensive Wistar rats. The experiment was repeated with 14-day ANGII infusion using Alzet osmotic mini pumps, with or without ANGII receptor AT1a inhibition using losartan in the drinking water. Mean arterial pressure increased after 2K1C or ANGII infusion and was inhibited with losartan. Heparin affinity chromatography and mass spectrometry were used to identify Annexin-A2 (ANXA2) as having differential nucleic acid-binding activity. Total Annexin-A2 protein expression was unchanged, whereas nucleic acid-binding activity was increased in both kidneys of 2K1C and after ANGII infusion through AT1a stimulation. Costaining of Annexin-A2 with α-smooth muscle actin and aquaporin 2 showed prominent expression in the endothelia of larger arteries and the cells of the inner medullary collecting duct. The nuclear factor of activated T cells (NFAT) transcription factor was identified as a likely Annexin-A2 target using enrichment analysis on a 2K1C microarray data set and identifying several binding sites in the regulatory region of the mRNA. Expression analysis showed that ANGII increases NFAT5 protein but not mRNA level and, thus, indicated that NFAT5 is regulated by posttranscriptional regulation, which correlates with activation of the RNA-binding protein Annexin-A2. In conclusion, we show that ANGII increases Annexin-A2 nucleic acid-binding activity that correlates with elevated protein levels of the NFAT5 transcription factor. NFAT signaling appears to be a major contributor to renal gene regulation in high-renin states.

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“…Despite complexities of the SHR, SHRSP and 2K1C hypertension models, a recent gene-expression profiling study revealed a common progression in hypertensive renal damage (Skogstrand et al, 2015). Of the 88 genes similarly regulated in all three models, 40 were also identified in gene-expression profiles from human fibrotic kidneys.…”

Section: Models Of Hypertensive Renal Damagementioning

confidence: 99%

Renal disease pathophysiology and treatment: contributions from the rat

Mullins

Conway

Menzies

et al. 2016

Disease Models &Amp; Mechanisms

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The rat has classically been the species of choice for pharmacological studies and disease modeling, providing a source of high-quality physiological data on cardiovascular and renal pathophysiology over many decades. Recent developments in genome engineering now allow us to capitalize on the wealth of knowledge acquired over the last century. Here, we review rat models of hypertension, diabetic nephropathy, and acute and chronic kidney disease. These models have made important contributions to our understanding of renal diseases and have revealed key genes, such as Ace and P2rx7, involved in renal pathogenic processes. By targeting these genes of interest, researchers are gaining a better understanding of the etiology of renal pathologies, with the promised potential of slowing disease progression or even reversing the damage caused. Some, but not all, of these target genes have proved to be of clinical relevance. However, it is now possible to generate more sophisticated and appropriate disease models in the rat, which can recapitulate key aspects of human renal pathology. These advances will ultimately be used to identify new treatments and therapeutic targets of much greater clinical relevance.

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Identification of a common molecular pathway in hypertensive renal damage

Abstract: There is a common pathway during the development of hypertensive kidney damage in rats irrespective of model. Interestingly, large parts of this common pathway are conserved in human kidney damage, which may indicate a broader importance in the development of chronic kidney disease.

Cited by 7 publications

References 38 publications

Proteomic Analysis of Minimally Damaged Renal Tubular Tissue from Two-Kidney-One-Clip Hypertensive Rats Demonstrates Extensive Changes Compared to Tissue from Controls

Proteomic Analysis of Minimally Damaged Renal Tubular Tissue from Two-Kidney-One-Clip Hypertensive Rats Demonstrates Extensive Changes Compared to Tissue from Controls

NFAT5 regulates renal gene expression in response to angiotensin II through Annexin-A2-mediated posttranscriptional regulation in hypertensive rats

Renal disease pathophysiology and treatment: contributions from the rat

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