Biomedical subjects

Jeremiah Morrissey

Publications and source records attributed to Jeremiah Morrissey.

11 recordsLinked to original sources

PubMed2004

L-arginine as a therapeutic tool in kidney disease.

Infusion of L-arginine in experimental animals increases renal plasma flow (RPF) and glomerular filtration rate (GFR). It is likely that a component of these hemodynamic changes are mediated by nitric oxide (NO) as suggested by studies with specific antagonists of L-arginine metabolism. L-arginine administration ameliorates the infiltration of the renal parenchyma by macrophages in rats with obstructive nephropathy or rats with puromycin-induced nephrotic syndrome. L-arginine administration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water had a greater GFR and RPF. L-arginine administration also decreased proteinuria. Diabetic rats given L-arginine had significantly lower excretion of protein and cyclic guanosine monophosphate than diabetic rats not receiving L-arginine. Despite persistent hyperglycemia, the administration of L-arginine prevented the development of hyperfiltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic acute renal failure, the administration of L-arginine had a beneficial effect on GFR and RPF, decreased O2- production, diminished up-regulation of soluble guanylate cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharmacokinetics of L-arginine indicate that side effects are rare and mostly mild and dose dependent.

Animals↗

PubMed2003

Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy.

BACKGROUND: Bone morphogenic protein-7 (BMP-7), an essential developmental renal morphogen, is a secreted differentiation factor of the adult collecting duct. It activates receptors in the collecting duct, distal nephron, proximal tubule, and glomerulus. BMP-7 is therapeutic in tubulointerstitial nephritis raising the question of broader efficacy in chronic kidney disease (CKD). METHODS: Diabetes was induced in 200 g rats by a single dose of streptozotocin. After 16 weeks, glomerular hypertrophy and proteinuria were established, and therapy with BMP-7 (10, 30, or 100 microg/kg intravenously twice a week), enalapril (20 mg/kg), or vehicle was begun and continued until 32 weeks. Kidney weight, glomerular filtration rate (GFR), urine albumin excretion, blood pressure, pathology, and BMP-7 expression were measured. RESULTS: Diabetic vehicle-treated rats developed renal insufficiency by 32 weeks (GFR, 0.34 +/- 0.02 mL/min/100 g body weight vs. 0.55 +/- 0.02 in normal). In the diabetic BMP-7 high-dose-treated rats, GFR was preserved (0.70 +/- 0.08, P < 0.01 vs. vehicle), and higher than diabetic enalapril-treated rats (0.58 +/- 0.06). Kidney weights of vehicle-treated animals were not affected, but were reduced in all of the treatment groups (P < 0.001). Proteinuria was reversed to normal by BMP-7 in a dose-dependent manner. The reduction in proteinuria by the intermediate dose of BMP-7 was similar to the effect of enalapril therapy. Glomerular area and interstitial volume were significantly decreased in the BMP-7 and enalapril-treated animals. Glomerular sclerosis was prevented by BMP-7 therapy more effectively than by enalapril. Enalapril controlled hypertension throughout the course of therapy while BMP-7 did not affect blood pressure until the final 4 weeks of therapy. Diabetic vehicle-treated rats lost BMP-7 expression in the kidney. BMP-7 and enalapril therapy restored BMP-7 expression at high levels. CONCLUSION: BMP-7 partially reversed diabetic-induced kidney hypertrophy, restoring GFR, urine albumin excretion, and glomerular histology toward normal. Restoration of BMP-7 expression was associated with a successful repair reaction and a reversal of the ill-fated injury response.

Albuminuria↗

PubMed2003

Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor.

BACKGROUND: The nephropathy induced by ureteral obstruction is associated with increased interstitial volume due to matrix deposition, fibroblast differentiation/proliferation, and monocyte infiltration. Recent studies indicate that transforming growth factor-beta (TGF-beta) is linked to renal fibrosis. Tumor necrosis factor (TNF-alpha) has a role in the recruitment of inflammatory cells. We found that infiltration of macrophages of the interstitium in unilateral ureteral obstruction (UUO) occurred as early as four hours after the onset of UUO. METHODS: Recent studies indicate that a renal tubular development morphogen, bone morphogenetic protein-7 (BMP-7), is effective in preventing the tubulointerstitial nephritis in the setting of obstructive nephropathy. The mechanism of action appears to be preservation of epithelial cell phenotype, inhibition of epithelial-mesenchymal transdifferentiation, and inhibition of injury-induced epithelial cell apoptosis. Hepatocyte growth factor (HGF) also inhibited tubulointerstitial fibrosis. RESULTS: In a treatment protocol in rats with ureteral ligation, BMP-7 restored renal function. The preservation of glomerular filtration rate (GFR) was accompanied by a significant decrease in cortical interstitial volume. In diabetic rats given BMP-7 proteinuria was normalized. In mice with ureteral obstruction, HGF suppressed the expression of TGF-beta and of platelet-derived growth factor. The onset of tubulointerstitial fibrosis was almost completely inhibited by HGF. CONCLUSION: Both BMP-7 and HGF attenuate the tubulointerstitial fibrosis due to ureteral obstruction. They also increase GFR and renal plasma flow.

Animals↗

PubMed2003

Progression of chronic renal disease.

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.

Angiotensin II↗

PubMed2003

ACE inhibition increases expression of the ETB receptor in kidneys of mice with unilateral obstruction.

Unilateral ureteral obstruction (UUO) is a well-established model for the study of interstitial fibrosis in the kidney. It has been shown that the renin-angiotensin system plays a central role in the progression of interstitial fibrosis. Recent studies indicate that endothelin, a powerful vasoconstrictive peptide, may play an important role in some types of renal disease. To investigate the effects of angiotensin II on endothelin and its receptors in the kidney, mice were subjected to UUO and treated with or without enalapril, an orally active angiotensin-converting enzyme inhibitor, in their drinking water (100 mg/l). The animals were killed 5 days later. Using RT coupled with PCR, we measured the levels of endothelin-1, endothelin A, and endothelin B (ET(B)) along with transforming growth factor-beta, TNF-alpha, and collagen type IV mRNA expression in the kidney with UUO and the contralateral kidney along with interstitial expansion in the kidney cortex by a standard point counting method. We found that enalapril administration ameliorated the increased expression of ET-1 mRNA in the obstructed kidney by 44% (P < 0.02). Although the level of endothelin A mRNA expression was significantly increased in the obstructed kidney, it was not affected by enalapril. We found that enalapril treatment increased ET(B) mRNA expression by 115% (P < 0.05) and protein expression (measured by Western blot) in the kidney with an obstructed ureter. Enalapril treatment alone inhibited the expansion of interstitial volume due to UUO by 52%. Cotreatment with enalapril and the ET(B) receptor antagonist BQ-788 inhibited the expression of interstitial volume by only 19%. This study confirms that enalapril inhibits the interstitial fibrosis in UUO kidneys. It also suggests a beneficial and unforeseen effect of enalapril on the obstructed kidney by potentially stimulating the production of nitric oxide through an increased expression of the ET(B) receptor.

Angiotensin II↗

PubMed2002

New approaches to delay the progression of chronic renal failure.

BACKGROUND: The molecular cloning of many bone morphogenetic proteins (BMP)-encoding genes and their identification as transforming growth factor-beta (TGF-beta) relatives enhanced the interest in these molecules and allowed expression and functional studies to be performed. METHODS: Rats with ureteral obstruction were distributed into four groups. Group 1 received vehicle, group 2 received enalapril 12.5 mg/kg body wt/day, group 3 received 50 or 300 microg/kg body wt BMP-7, and group 4 received both enalapril and the high dose of BMP-7. We also studied the effects of BMP-7 administration in a model streptozocin-induced diabetes. RESULTS: Treatment with BMP-7 in rats with ureteral obstruction of 3 days duration and subsequent release indicated that this compound decreases interstitial volume and accelerates the return of renal function. After 16 weeks of diabetes, the rats were treated with BMP-7. The administration of BMP-7 partially reversed renal hypertrophy, restored GFR to normal, and decreased proteinuria. CONCLUSIONS: These studies indicate that administration of BMP-7 maintains and restores renal function and structure in animals with ureteral obstruction and diabetic nephropathy.

Animals↗

PubMed2002

Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage.

Angiotensin II (Ang II) regulates a number of genes associated with progression of renal disease. The regulation of gene expression by Ang II occurs through specific receptors that are linked to changes in the activity of transcription factors within the nucleus of target cells. In particular, members of the nuclear factor-kappaB family of transcription factors are activated, which in turn fuels at least two autocrine reinforcing loops that amplify Ang II and tumor necrosis factor-alpha formation. Angiotensin converting enzymes (ACE) inhibitors and angiotensin antagonists (AIIAs) differ both pharmacokinetically and pharmacodynamically in patients with end-stage renal disease (ESRD). Several ACE inhibitors (such as captopril, enalapril and lisinopril) are dialyzable, whereas all of the AIIAs studied are not. Dose titration may be necessary when administering ACE inhibitors to patients with renal failure (ESRD), but is rarely a consideration when AIIAs are used.

Angiotensin II↗

PubMed2002

Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease.

For elucidation of the mechanisms by which growth factors and cytokines affect renal epithelial cells, gene array analysis of renal cells cultured in the presence of transforming growth factor-beta1 (TGF-beta1) was performed. Many genes that were not previously considered to be involved in renal cell biologic processes were affected, one of which was jagged-1. The jagged ligand/notch receptor family controls the formation of boundaries between groups of cells and regulates cell fates. On the basis of the array analysis, jagged-1 expression was further evaluated in cultured cells and in C57BL/6 mice with a model of unilateral ureteral obstruction (UUO). Recombinant human TGF-beta1 increased jagged-1 mRNA levels at concentrations between 10(-11) and 10(-10) M. There was a commensurate increase in jagged-1 protein levels, as assessed by Western blotting. The expression of jagged-1 mRNA and protein was observed to be significantly increased in the kidneys of C57BL/6 mice with obstructed ureters, compared with the contralateral kidneys, at 7 and 14 d of UUO. Immunohistochemical analyses demonstrated jagged-1 expression in distal tubules of kidneys from normal mice or contralateral kidneys from mice with UUO. Jagged-1 protein expression was increased in tubules not yet in apparent atrophy in the kidneys with an obstructed ureter. Jagged-1 expression was significantly increased in the kidneys of normal mice treated with TGF-beta1 and was decreased in the kidneys of mice with UUO treated with a TGF-beta receptor II-Fc chimera. These results suggest that jagged-1 is expressed in normal kidneys and that this expression is upregulated during renal disease, in a TGF-beta-dependent manner.

Animals↗

PubMed2002

Obstructive nephropathy and renal fibrosis.

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

Animals↗

PubMed2002

Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function.

A prevention protocol has demonstrated that bone morphogenetic protein-7 (BMP-7) blunted the development of fibrosis in a rat model of unilateral ureteral obstruction. This prevention protocol also preserved, to an extent, renal function. The prevention protocol was extended and a treatment protocol used to examine if BMP-7 was beneficial at limiting fibrosis of the kidney when the BMP-7 was administered during the progression of fibrotic disease. Animals were distributed into four groups. Group 1 received vehicle, group 2 received enalapril (12.5 mg/kg body wt per d), group 3 received BMP-7 (50 or 300 microg/kg), and group 4 received both the enalapril and the high dose of BMP-7. Rats underwent reversible unilateral ureteral obstruction for 3 d, after which the obstruction was relieved. In the treatment protocol, 300 microg/kg BMP-7 was given after the release of obstruction. Seven days after release of the obstruction and the onset of treatment glomerular filtration rate (GFR), renal blood flow, and various histologic indexes of fibrosis were determined. On a consistent basis, BMP-7 treatment alone was found to be slightly but significantly (P < 0.04 to 0.007) better than enalapril alone or in combination with enalapril at decreasing interstitial volume or tubule atrophy. BMP-7 treatment was slightly but not significantly better (P < 0.09) than enalapril at restoring GFR in the prevention protocol. Treatment with BMP-7 significantly boosted GFR (P < 0.01) above that seen with vehicle treatment. These results suggest that BMP-7 treatment is capable of blunting the progression of fibrotic disease and of decreasing interstitial volume. Importantly, a return of renal function is accelerated by BMP-7 treatment. These results suggest that administration of BMP-7 may be an effective treatment to restore or preserve renal histology and renal function in this experimental model of renal disease.

Animals↗

PubMed2000

Induction of CD14 in tubular epithelial cells during kidney disease.

Analysis of gene expression in a mouse model of unilateral ureteral obstruction (UUO) revealed significant induction of CD14 mRNA in kidneys with obstructed ureters. Immunocytochemical analysis indicated that CD14 was upregulated in tubular epithelial cells and this upregulation was not attributable to infiltration of the kidneys by mononuclear cells. This induction of CD14 mRNA was found to occur in BALB/C, C57BL/6, C3H/HeN, and C3H/HeJ mice during UUO. Ischemia/reperfusion of kidneys also induced CD14 mRNA. Mice lacking either of the tumor necrosis factor-alpha receptor (TNFR) genes were also studied; the induction of CD14 was blunted in TNFR 1-knockout mice but not in TNFR2-knockout mice. Apoptosis of tubular cells in lipopolysaccharide-resistant CH3/HeJ mice was significantly (P: < 0. 05) less than that in lipopolysaccharide-responsive CH3/HeN mice during UUO. These results suggest that CD14 is acutely induced in tubular epithelial cells in two mouse models of renal injury. This induction is regulated by tumor necrosis factor-alpha, through TNFR1. CD14 may participate in the apoptosis of tubular epithelial cells on a more chronic basis by activating a pathway that is absent or deficient in C3H/HeJ mice.

Animals↗