Biomedical subjects

Saulo Klahr

Publications and source records attributed to Saulo Klahr.

26 records · Page 2Linked to original sources

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

Renal physiology between two wars: the contributions of Dr. Harvey Lester White.

Harvey Lester White (1896-1977) graduated from Washington University (St. Louis) School of Medicine and subsequently spent his entire professional career in the School's Department of Physiology. White's interest in the function of the kidney was evident early in his academic career when he pioneered research related to renal physiology. His first papers dealt with studies of renal tubular function (1923). He performed what appear to represent the first micropuncture studies in the kidney of Necturus maculosus (1926) and thus confirmed the observations of Wearn and Richards regarding glomerular filtration. Through these studies, he was the first to show that glucose reabsorption occurs in the proximal tubules of Necturus. It also appears that White et al. were the first to demonstrate that volume expansion increases bicarbonate excretion in dogs (1926). He studied the influence of posture on renal "activity" in man (1926). Intracapsular pressure determinations in Necturus kidney (1928) were done using micropuncture techniques. White and co-workers presented (1933) a comparison of clearances of creatinine and various sugars confirming the work of Jolliffe, Shannon and Smith (1932) who had proposed the clearances of non-metabolizable sugars to be a measure of glomerular filtration. Between 1932 and 1936, in an effort to better understand the process of glomerular filtration, he began a series of studies on streaming potentials, surface conductance, electro-endosmosis and other related topics. In 1937, White began work on yet another aspect of renal physiology--endocrine influences on renal function. He would immerse himself in these investigations throughout the remainder of his scientific career. We hope that this account will reveal at least a small dimension of the man and his contributions to renal physiology.

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↗

PubMedDate not supplied

The bone morphogenetic proteins (BMPs). Their role in renal fibrosis and renal function.

Recently, a protein has emerged as a potential renotrophic factor: bone morphogenetic protein-7 (BMP-7). In a preventive protocol, BMP-7 treatment was found to significantly decrease renal injury in a rat model of ureteral obstruction (UUO), when treatment was initiated at the time of injury. Subsequent studies suggested that BMP-7 treatment also attenuated renal fibrosis when administered after renal fibrosis had begun. This treatment protocol was also found to increase significantly renal function from the levels measured in the vehicle-treated group. BMP-7 also partially reversed the diabetic nephropathy induced in rats by a single dose of streptozotocin. It restored glomerular filtration rate (GFR), decreased the excretion of protein, and restored histology towards normal. These studies also highlight the value of histological parameters as indicators of renal function and the potential of renal homeostatic factors in the treatment of kidney disease.

Acute Kidney Injury↗