Arachidonic acid (AA) is metabolized by enzymes of the CYP4A and 4F families to 20-hydroxyeicosatetraeonic acid (20-HETE) which plays an important role in the regulation of renal function, vascular tone and the long term control of arterial pressure. In the vasculature, 20-HETE is a potent vasoconstrictor and upregulation of the production of this compound contributes to the elevation in oxidative stress, endothelial dysfunction and the increase in peripheral vascular resistance associated with some forms of hypertension. In kidney, 20-HETE inhibits Na+ transport in the proximal tubule and thick ascending loop of Henle and deficiencies in the renal formation of 20-HETE contributes to sodium retention and the development of some salt-sensitive forms of hypertension. 20-HETE also has renoprotective actions and opposes the effects of transforming growth factor (TGF-β) to promote proteinuria and renal end organ damage in hypertension. Several new inhibitors of the synthesis of 20-HETE and 20-HETE agonists and antagonists have recently been developed. These compounds along with PPAR-α agonists that induce the renal formation 20-HETE appear to have promise as antihypertensive agents. This review summarizes the rationale for the development of drugs that target the 20-HETE pathway for the treatment of hypertension and associated cardiovascular complications.
Diabetes and hypertension are the leading causes of chronic kidney disease and their incidence is increasing at an alarming rate. Both are associated with impairments in the autoregulation of renal blood flow (RBF) and greater transmission of fluctuations in arterial pressure to the glomerular capillaries. The ability of the kidney to maintain relatively constant blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure is mediated by the myogenic response of afferent arterioles working in concert with tubuloglomerular feedback that adjusts the tone of the afferent arteriole in response to changes in the delivery of sodium chloride to the macula densa. Despite intensive investigation, the factors initiating the myogenic response and the signaling pathways involved in the myogenic response and tubuloglomerular feedback remain uncertain. This review focuses on current thought regarding the molecular mechanisms underlying myogenic control of renal vascular tone, the interrelationships between the myogenic response and tubuloglomerular feedback, the evidence that alterations in autoregulation of RBF contributes to hypertension and diabetes-induced nephropathy and the identification of vascular therapeutic targets for improved renoprotection in hypertensive and diabetic patients.
This study examined the effect of substitution of a 2.4-megabase pair (Mbp) region of Brown Norway (BN) rat chromosome 1 (RNO1) between 258.8 and 261.2 Mbp onto the genetic background of fawn-hooded hypertensive (FHH) rats on autoregulation of renal blood flow (RBF), myogenic response of renal afferent arterioles (AF-art), K ϩ channel activity in renal vascular smooth muscle cells (VSMCs), and development of proteinuria and renal injury. FHH rats exhibited poor autoregulation of RBF, while FHH.1BN congenic strains with the 2.4-Mbp BN region exhibited nearly perfect autoregulation of RBF. The diameter of AF-art from FHH rats increased in response to pressure but decreased in congenic strains containing the 2.4-Mbp BN region. Protein excretion and glomerular and interstitial damage were significantly higher in FHH rats than in congenic strains containing the 2.4-Mbp BN region. K ϩ channel current was fivefold greater in VSMCs from renal arterioles of FHH rats than cells obtained from congenic strains containing the 2.4-Mbp region. Sequence analysis of the known and predicted genes in the 2.4-Mbp region of FHH rats revealed amino acid-altering variants in the exons of three genes: Add3, Rbm20, and Soc-2. Quantitative PCR studies indicated that Mxi1 and Rbm20 were differentially expressed in the renal vasculature of FHH and FHH.1BN congenic strain F. These data indicate that transfer of this 2.4-Mbp region from BN to FHH rats restores the myogenic response of AF-art and autoregulation of RBF, decreases K ϩ current, and slows the progression of proteinuria and renal injury. kidney; glomerulosclerosis; chronic renal failure; renal hemodynamics THE FAWN-HOODED HYPERTENSIVE (FHH) rat is a genetic model of hypertension (33) that develops proteinuria, glomerulosclerosis (21,30,37,47), and chronic kidney disease (22,(25)(26)(41)(42). We have previously reported that the development of proteinuria and glomerular injury in FHH rats is associated with an impaired autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR), and glomerular capillary pressure (Pgc) (24,40,43,48). Genetic cosegregation studies identified five quantitative trait loci (QTLs) linked to the development of proteinuria in F2 crosses of FHH and AugustCopenhagen inbred (ACI) rats (4 -5, 36). The rat chromosome (RN) regions are Rf-1 and Rf-2 on RNO1, Rf-3 on RNO3, Rf-4 on RNO14, and Rf-5 on RNO17. The Rf-1 QTL is of particular interest in that it lies within a region that is homologous to an area on human chromosome 10 linked to the development of diabetic nephropathy (19) and end-stage renal disease (18). More recent studies identified a G-to-A mutation in the start codon of Rab38, a gene in the Rf-2 QTL that influences protein trafficking and contributes to the development of proteinuria in FHH rats (32). However, the genes in the Rf-1 region that contribute to the development of proteinuria and renal disease in FHH rats and the mechanisms involved are unknown.We have previously reported that substitution of a 99.4-megabase pair (Mbp) reg...
Small Cajal body-specific RNAs (scaRNAs) are part of small Cajal body-specific ribonucleoproteins (scaRNPs) that modify small nuclear RNA (snRNA) in Cajal bodies (CBs). Several scaRNAs (scaRNA 2, 9 and 17) have been found to generate smaller, nucleolus-enriched fragments. We hypothesize that the fragments derived from scaRNA 2, 9 and 17 form regulatory RNPs that influence the level of modifications within rRNA by altering small nucleolar RNP (snoRNP) activity. Here we show that external factors such as DNA damaging agents can alter the scaRNA9 full length to processed fragment ratio. We also show that full-length scaRNA2 levels are likewise impacted by DNA damage, which correlates with the disruption of SMN, coilin and WRAP53 co-localization in CBs. The dynamics of scaRNA9 were also shown to be affected by Drosha levels, which suggests that this protein may participate in the biogenesis and processing of this non-coding RNA. Identification of factors that contribute to scaRNA 2, 9 and 17 processing may facilitate an assessment of how external stress can lead to changes in rRNA modifications.
The present study examined the effect of transfer of portions of chromosome 1 that includes (FHH.1(BN) AR(+) strain) or excludes (control FHH.1(BN) AR(-) strain) a 4.3-Mb region from the Brown Norway (BN) rat that restores the autoregulation (AR) of renal blood flow (RBF) on the development of hypertension and renal injury in congenic strains of Fawn Hooded Hypertensive (FHH) rats. FHH and control AR(-) rats exhibited poor autoregulation of RBF, and glomerular capillary pressure (Pgc) rose by 19 ± 2 mmHg in FHH rats when renal perfusion pressure (RPP) was increased from 100 to 150 mmHg. In contrast, RBF was well autoregulated in the AR(+) strain, and Pgc only increased by 3 ± 1 mmHg when RPP was increased over this range. Baseline mean arterial pressure (MAP) at 12 wk of age was similar in all strains and averaged 122 mmHg. MAP increased significantly in FHH rats and was significantly higher by 12 mmHg in 21-wk-old FHH rats than in the FHH.1(BN) congenic strains. Protein excretion rose from 5 ± 1 to 397 ± 29 mg/day in 6- vs. 21-wk-old FHH rats. In contrast, protein excretion only increased to 139 ± 21 mg/day in the control AR(-) strain, and it did not increase significantly in the AR(+) strain. Glomerular permeability to albumin was similar in all strains at 6 wk of age. It increased significantly in 9-wk-old FHH and control AR(-) rats, but not in the AR(+) strain. The levels of matrix metalloproteinase (MMP)-2 and transforming growth factor (TGF)-β2 protein were significantly higher in the renal cortex of 9-wk-old FHH rats compared with the levels seen in the AR(+) strain. These data indicate that transfer of a 4.3-Mb region of BN chromosome 1 into the FHH genetic background improves autoregulation of RBF, normalizes Pgc, and slows the progression of renal disease.
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