Tetsuo Katoh

Amelioration of Genetic Hypertension by Suppression of Renal G Protein-Coupled Receptor Kinase Type 4 Expression

Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein–coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar–Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were ≈90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN–treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.

Increased Expression of Parathyroid Hormone–Related Peptide Gene in Blood Vessels of Spontaneously Hypertensive Rats

We have shown recently that mechanical stretch of cultured rat aortic smooth muscle cells induces a marked increase in gene expression of the vasorelaxant parathyroid hormone-related peptide. In the present study, we investigated whether mechanical force affected the in vivo parathyroid hormone-related peptide gene expression in blood vessels. Northern blot analysis revealed that stretch of isolated rat aortic strips increased the expression level of parathyroid hormone-related peptide mRNA. The parathyroid hormone-related peptide transcript level in aorta and mesenteric vessels from 18-week-old spontaneously hypertensive rats (SHR) was 2.5- and 2.2-fold higher, respectively, compared with age-matched Wistar-Kyoto (WKY) controls, whereas the parathyroid hormone-related peptide mRNA level in aorta from normotensive 4-week-old SHR was similar to that of age-matched WKY controls. The aortic parathyroid hormone-related peptide content was higher in 18-week-old SHR than in age-matched WKY controls. Moreover, treatment of mature SHR with an angiotensin II type 1 receptor antagonist or hydralazine caused a concomitant decrease in the parathyroid hormone-related peptide transcript level in aorta with lowering of blood pressure. These results suggest that the in vivo parathyroid hormone-related peptide gene expression in blood vessels is under the control of mechanical force, pointing to a role of parathyroid hormone-related peptide in the regulation of vascular tone.

Serum hepatocyte growth factor concentration in patients with various degrees of chronic renal failure

Summary: Serum hepatocyte growth factor (HGF) concentrations were measured in healthy volunteers, chronic renal failure patients without renal replacement therapy and haemodialysis patients. Serum HGF concentrations in healthy volunteers, chronic renal failure patients and haemodialysis patients were 0.18 ± 0.04 (s.d.), 0.28 ± 0.06 and 0.46 ± 0.22 ng/mL, respectively. Serum HGF concentration in chronic renal failure patients was significantly higher than that in healthy volunteers. Serum HGF concentration in haemodialysis patients was significantly higher than those in healthy volunteers and chronic renal failure patients. There was no regression of serum HGF concentration on age, sex, history of haemodialysis, prehaemodialysis serum creatinine concentration, and serum tumour necrosis factor (TNF)‐α concentration. We conclude that chronic renal disease and haemodialysis therapy are contributing factors to an increased serum HGF concentration.