Renoprotective Effect of Chronic Adrenomedullin Infusion in Dahl Salt-Sensitive Rats

Abstract

Abstract-The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor ␤ (TGF-␤) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine Ϫ87%, creatinine clearance ϩ114%, urinary protein excretion Ϫ59%) and histological findings (glomerular injury score Ϫ54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (Ϫ97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (Ϫ269%), aldosterone level (Ϫ82%), and renal tissue angiotensin II levels (Ϫ60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-␤ (Ϫ63%), angiotensin-converting enzyme (Ϫ137%), renin (Ϫ230%), and angiotensinogen (Ϫ38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system. Key Words: adrenomedullin Ⅲ hypertension, experimental Ⅲ rats, Dahl Ⅲ renin-angiotensin system Ⅲ transforming growth factors A drenomedullin (AM) is a novel vasodilatory peptide originally discovered in human pheochromocytoma tissue. 1 Subsequent studies demonstrated that AM is widely distributed in the cardiovascular system, including the kidney, heart, lungs, and blood vessels. 1 AM gene transcripts and specific binding sites for this peptide are also present at high levels in the kidney, heart, lungs, and blood vessels. 2 Immunohistochemistry of AM in the canine kidney has revealed AM immunoreactivity in glomeruli, cortical distal tubules, and medullary collecting duct cells. 3 These results suggest that AM may play a role in the regulation of kidney function. Indeed, intrarenal infusion of AM increased the renal blood flow (RBF) and glomerular filtration rate (GFR) and lowdose intrarenal infusion of AM increased the urinary flow and sodium excretion without changes in GFR. 3 These effects are mediated by AM binding to a G...

Haplotype-Based Case-Control Study Revealing an Association between the Adrenomedullin Gene and Proteinuria in Subjects with Essential Hypertension

“…The investigators themselves pointed out that the frequency of the 19-repeat allele of the microsatellite was not increased in hypertensive diabetic patients without nephropathy, which decreases the likelihood that the relationship between the 19-repeat allele and diabetic nephropathy is mediated by a predisposition to hypertension. AM has been reported to play a renoprotective role in chronic hypertensive renal failure (28), and the plasma and urinary AM levels in patients with chronic glomerulonephritis have been shown to reflect the disease activity or glomerular damage represented by the degree of PU (29). Overall these results suggest that AM is involved in the pathophysiology of renal function or PU.…”

Enhancement of Intrarenal Angiotensinogen in Dahl Salt-Sensitive Rats on High Salt Diet

“…However, recent studies suggest that treatment with Ang I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rats made hypertensive by a HS diet. [5][6][7][8][9][10] Furthermore, Nakaya et al 15 reported that prepubertal treatment with an Ang II type I receptor antagonist causes partial attenuation of hypertension and ameliorates the renal damage in adult DS rats fed HS. These data suggest that the local RAS may contribute to development of hypertension and renal dysfunction in this model.…”

“…Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin (Ang) I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rat fed a high salt diet (HS). [5][6][7][8][9][10] These findings suggest that the local RAS may be inappropriately activated and contribute to the development of hypertension in this animal model.Previous studies have demonstrated that Ang II infusions to normal rats result in paradoxical increases in renal expression of AGT mRNA 11,12 and protein. 13 Furthermore, urinary excretion of AGT was significantly increased in Ang II-infused rats, which was associated with an enhancement of intrarenal Ang II levels.…”

“…Although generally considered to be characterized by a low activity of circulating RAS, recent studies indicate that treatment with angiotensin (Ang) I-converting enzyme inhibitors or Ang II type I receptor antagonists reduces cardiac and/or renal dysfunction in DS rat fed a high salt diet (HS). [5][6][7][8][9][10] These findings suggest that the local RAS may be inappropriately activated and contribute to the development of hypertension in this animal model.…”

Cardioprotective Effect of Adrenomedullin in Heart Failure

“…These findings showed that AM gene delivery attenuates hypertension, protects against cardiac remodeling and renal damage in hypertension, and may have significance in therapeutic applications in cardiovascular and renal diseases. We also recently reported that chronic human AM infusion exerted renoprotective effects in a rat model of malignant hypertension (48,49). Human AM infusion significantly reduced plasma renin concentration, plasma aldosterone levels and plasma endogenous rat AM levels with a slight increase of plasma human AM levels.…”