Short stature and diabetic nephropathy.
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Adolescent↗
Biomedical subjects
B M Brenner
Publications and source records attributed to B M Brenner.
Fewer nephrons at birth: a missing link in the etiology of essential hypertension?
In 1988, Brenner et al advanced the hypothesis that the nephron endowment at birth is inversely related to the risk of developing essential hypertension in later life (Am J Hypertens 1:335-347, 1988). This novel perspective on the origins of essential hypertension was taken from the viewpoint that the development and maintenance of hypertension must involve a renal factor favoring sodium retention, thereby preventing pressure-induced natriuresis from restoring blood pressure toward normal levels. Since nephron numbers in the normal population range from 300,000 to 1,100,000 or more, it was reasoned that a congenital deficit in nephron endowment itself could be the renal risk factor for hypertension: demographic groups in whom hypertension is unusually prevalent tend to have smaller kidneys, implying fewer nephrons, and some inbred hypertensive rat strains have, on average, fewer nephrons than their respective normotensive controls. We argue that recent independent observations in humans relating low birth weight to both increased risk of hypertension in later life and the formation of fewer nephrons at birth lend strong support to the nephron number hypothesis. Moreover, independent experimental studies in rodents suggest that maternal protein intake during gestation is directly related to he numbers of nephrons formed and that when protein intake is restricted, the offspring develop hypertension in maturity. The concept that nephron numbers may be programmed during gestation, as these observations imply, is discussed in relation to the potential advantages and disadvantages of such a mechanism for the next generation; parallels are drawn with the relationship of low birth weight to pancreatic beta cell development and maturity-onset diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy.
Previous studies documented that single section examination of kidney tissue underestimates glomerulosclerosis and that three-dimensional examination of glomerular morphology improves recognition of the incidence and distribution of sclerotic changes within the glomerular capillary tuft. We have adopted this technique to evaluate the true frequency and the spatial extent of glomerulosclerosis in patients who were subjected to extensive renal mass reduction. We re-evaluated four kidney biopsies of patients with a solitary kidney who had undergone partial nephrectomy for renal-cell carcinoma. Histopathological examination aimed at detection of glomerular sclerotic lesions was performed on serial sections (from 75 to 93 serial sections for each biopsy, 3 microns thick) together with three-dimensional morphometric analysis of glomerular tuft and sclerotic areas using a computer-based image processing system. Results were compared with observations based on more conventional single section evaluation of the same biopsies. Among 65 glomeruli examined by three-dimensional morphometric analysis, only 8% were normal, 42% revealed segmental sclerosis and 51% global sclerosis. These results confirmed that single section evaluation grossly overestimates the number of normal glomeruli (37% vs. 8%, respectively), since the majority of glomeruli classified as normal are indeed affected by sclerotic changes in areas typically out of the section plane. The three-dimensional distribution of sclerosis is characterized by the appearance of multi-focal areas affecting a small capillary tuft volume (< 10%) which ultimately propagate to the entire capillary tuft. Despite the maintenance of renal function, at the time of biopsy in patients with extensive ablation of renal mass, the incidence of glomerulosclerosis affects almost the entire glomerular population.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopsy↗
ROMK inwardly rectifying ATP-sensitive K+ channel. II. Cloning and distribution of alternative forms.
The rat ROMK gene encodes inwardly rectifying, ATP-regulated K+ channels [K. Ho, C. G. Nichols, W. J. Lederer, J. Lytton, P. M. Vassilev, M. V. Kanazirska, and S. C. Hebert. Nature Lond. 362: 31-38, 1993; H. Zhou, S. S. Tate, and L. G. Palmer. Am. J. Physiol. 266 (Cell Physiol. 35): C809-C824, 1994], and mRNA encoding these channels is widely expressed in distal cortical and outer medullary nephron segments [see companion study; W.-S. Lee and S. C. Hebert. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F1124-F1131, 1995]. Using approaches based on homology to ROMK1, we have identified two additional ROMK isoforms, ROMK2b and ROMK3. Analysis of the nucleotide sequences of the ROMK isoforms indicates that molecular diversity of ROMK transcripts is due to alternative splicing at both the 5'-coding and 3'-noncoding regions. The splicing at the 5' end of ROMK gives rise to channel proteins with variable-length NH2 termini containing different initial amino acid sequences. Functional expression of these isoforms in Xenopus oocytes showed that they form functional Ba(2+)-sensitive K+ channels. The nephron distribution of mRNAs encoding alternatively spliced isoforms of ROMK (ROMK1-ROMK3) was investigated by reverse transcription-polymerase chain reaction (RT-PCR) of nephron segments dissected from rat kidney. Nondegenerate PCR primer pairs were designed to span at least one intron and to amplify specific alternatively spliced forms of ROMK.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Renal effects of high-dose natriuretic peptide receptor blockade in rats with congestive heart failure.
Previous studies suggest that elevated plasma atrial natriuretic peptide (ANP) levels participate in regulating renal excretory function in rats with congestive heart failure (CHF). To define the role of natriuretic peptides (NPs) in the regulation of renal function in CHF, the renal responses to HS-142-1 (HS), a potent NP receptor antagonist, were studied in anesthetized rats subjected to coronary ligation that developed left ventricular infarction and CHF or in sham-operated (SO) control rats. Plasma ANP levels averaged > 14-fold higher in rats with CHF than in SO rats. In response to HS (20 mg/kg IV bolus), both mean arterial pressure and renal vascular resistance increased in rats with CHF but not in SO rats; glomerular filtration rate (GFR, 1.26 +/- 0.04 versus 0.76 +/- 0.11 mL/min) and renal plasma flow rate (RPF, 3.52 +/- 0.27 versus 2.70 +/- 0.32 mL/min) were significantly reduced in rats with CHF; and in SO rats, GFR (1.26 +/- 0.06 versus 1.20 +/- 0.07 mL/min) and RPF (3.98 +/- 0.21 versus 3.99 +/- 0.18 mL/min) were not significantly affected by HS. The sodium excretion rate (0.18 +/- 0.04 to 0.06 +/- 0.01 muEq/min) and fractional sodium excretion (0.01 +/- 0.02% to 0.04 +/- 0.01%) also fell markedly after HS administration in rats with CHF, but these parameters were unchanged in SO rats. These data indicate that NPs play a critical role in maintaining renal hemodynamic function and inhibiting tubule sodium reabsorption in rats with CHF, thus opposing sodium retention and preserving sodium balance in this model.
Animals↗
Low birth weight. A risk factor for development of diabetic nephropathy?
It has been demonstrated that intrauterine growth retardation, defined as birth weight below the 10th percentile, gives rise to a reduction in nephron number. Oligonephropathy has been suggested to increase the risk for systemic and glomerular hypertension in adult life as well as enhance risk for expression of renal disease after exposure to potentially injurious renal stimuli. The aim of this study was to determine if low birth weight is a risk factor for development of diabetic nephropathy. In a case-control study, we investigated 184 (110 men) insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy (persistent albuminuria > 300 mg/24 h) (age [mean +/- SD] 41.0 +/- 9.3 years, duration of diabetes 26.9 +/- 8.2 years) and 182 (111 men) normoalbuminuric (< 30 mg/24 h) IDDM patients (age 42.1 +/- 9.8 years, duration of diabetes 25.8 +/- 8.6 years). Information about weight at birth was obtained from the midwife's original registrations. In women below the 10th percentile in birth weight (< or = 2,700 g, n = 16), 75% had nephropathy compared with only 35% among patients whose birth weights were above the 90th percentile (> or = 4,000 g, n = 17) (P = 0.05). In men below the 10th percentile in birth weight (< or = 2,910 g, n = 22), the prevalence of patients with nephropathy (50%) was similar to the prevalence among patients above the 90th percentile in birth weight (> or = 4,200 g, n = 24) (54%).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Influence of renal mass on chronic kidney allograft rejection in rats.
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Animals↗
The contribution of reduced functioning mass to chronic kidney allograft dysfunction in rats.
Chronic renal allograft dysfunction may become manifest months or years after transplantation by progressive functional deterioration associated with morphological changes that include vascular obliteration, glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Two hypotheses have evolved to explain the etiology of this process, usually described as "chronic rejection:" first, that it is primarily an antigen-dependent phenomenon influenced by continuing host alloresponsiveness; second, that nonimmunological, alloantigen-independent factors contribute to the progressive changes. Using an established model of chronic rejection of kidney transplants in rats in which the lesions progress relentlessly over time, we have determined the long-term effects of superimposing renal mass reduction on the indices of progressive allograft injury. Increasing proteinuria, a reproducible index of kidney graft dysfunction, developed after 12 weeks in all recipients of intact allografts, but was accelerated in kidneys with reduced mass, regardless of whether the organ was allogeneic or isogeneic. The coincident infiltration of macrophages and expression of cytokines and growth factors were associated with the development of glomerular sclerosis and interstitial fibrosis; such functional and morphological alterations occurred in an accelerated manner in all reduced-mass kidney allografts and isografts. Conversely, intact allografts in recipients also bearing a retained native kidney never manifested any chronic changes throughout the entire follow-up period. These findings emphasize the role of alloantigen-independent factors, particularly reduced renal mass, in the multi-factorial etiology of "chronic rejection" of kidney transplants.
Animals↗
Renal effects of natriuretic peptide receptor blockade in cirrhotic rats with ascites.
The aim of this study was to assess the effect of HS-142-1, a recently discovered specific antagonist of endogenous natriuretic peptides, on systemic hemodynamics, renal function, and the renin-aldosterone system in rats with cirrhosis and ascites. The study consisted of three protocols, each including 10 conscious control rats and 10 conscious rats with carbon-tetrachloride-induced cirrhosis with ascites. In protocol 1, HS-142-1 administration (by intravenous bolus of 20 mg.kg-1.body weight in all protocols) was not associated with significant changes in mean arterial pressure, heart rate, cardiac output or total peripheral resistance in the two groups of animals. In protocol 2, HS-142-1 induced a significant reduction in glomerular filtration rate (from 4.2 +/- 0.5 to 2.6 +/- 0.3 ml/min, p < 0.025) in control animals. A decrease in renal plasma flow and an increase in renal vascular resistance also occurred, but these changes were not statistically significant. In cirrhotic rats, HS-142-1 resulted in a significant decrease in renal plasma flow (from 10.9 +/- 0.7 to 4.3 +/- 0.6 ml/min, p < 0.001) and a significant increase in renal vascular resistance (from 6.0 +/- 0.6 to 16.3 +/- 2.7 mm Hg.min.ml-1, p < 0.025). Glomerular filtration rate decreased more in cirrhotic rats with ascites than in control rats (from 3.8 +/- 0.3 to 1.3 +/- 0.2 ml/min, p < 0.001). Changes in urine flow rate and urinary sodium excretion rate paralleled those of glomerular filtration rate in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Modulation of glomerular hypertension defines susceptibility to progressive glomerular injury.
The fawn-hooded rat constitutes a spontaneous model for chronic renal failure with early systemic and glomerular hypertension, proteinuria (UpV) and high susceptibility to development of focal and segmental glomerular sclerosis (FGS). It has been argued that uninephrectomy (UNX) accelerates the development of glomerular injury by aggravation of glomerular hypertension and by an independent effect to promote glomerular enlargement. The present study was performed to further delineate the importance of these parameters for the development of FGS. At the age of eight weeks male rats were UNX and randomly assigned to either control (CON), enalapril (ENA) or Nw-nitro L-arginine methyl ester (NAME) treatment. In all groups glomerular hemodynamic studies were performed four weeks post-UNX. Systemic blood pressure and UpV were monitored for 4 to 12 weeks post-UNX. Kidneys were then prepared for morphologic study. ENA treatment achieved control of both systemic and glomerular hypertension, maintenance of glomerular hyperfiltration and hyperperfusion, increased ultrafiltration coefficient(Kf), and long-term protection against UpV and FGS. NAME rats showed aggravation of both systemic and glomerular hypertension, decreased renal perfusion and filtration with reduced Kf, and high filtration fraction. The incidence of FGS in NAME and CON groups was similar at 8 and 12 weeks post-UNX, respectively. Glomerular enlargement was present in CON and ENA rats, but did not correlate with injury, while glomerular tuft size was lowest in NAME rats, which displayed prominent glomerular injury. Systemic blood pressure correlated strongly with glomerular capillary pressure. We conclude that systemic and glomerular hypertension govern the development of UpV and FGS.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats.
To identify the contribution of natriuretic peptide (NP) activity to the adaptative increases in glomerular filtration rate (GFR), effective renal plasma flow rate (ERPF) and fractional sodium excretion (FENa) observed in the remnant kidney, we investigated the acute effects of administering HS-142-1 (HS), a potent NP receptor antagonist, in 5/6th nephrectomized (NPX) rats. In addition to normal sodium intake, high or low sodium intakes were used to stimulate or suppress, respectively, endogenous NP activity in NPX rats. In rats three days after NPX on high sodium, HS (20 mg/kg bolus i.v.) reduced GFR from 0.55 +/- 0.05 to 0.35 +/- 0.04 ml/min; ERPF from 1.83 +/- 0.19 to 1.53 +/- 0.16 ml/min; and FENa from 7.1 +/- 1.1 to 1.6 +/- 0.4%, without affecting MAP. Similar changes of lesser magnitude were observed in NPX rats on normal sodium intake. By contrast, GFR, ERPF, FENa and MAP were unchanged following HS in NPX rats on low sodium intake, suggesting that the magnitude of responses to HS is dependent upon the expected levels of activity of NP. We conclude that in anesthetized rats, natriuretic peptides contribute to the compensatory increases in GFR, ERPF and FENa observed in the remnant kidney under normal and salt-replete conditions.
Adaptation, Physiological↗
Coordinate regulation of 11 beta-HSD and Ke 6 genes in cpk mouse: implications for steroid metabolic defect in PKD.
Polycystic kidney disease (PKD) is characterized by multiple renal cysts, which ultimately result in renal failure. We have reported the identification of a new gene, Ke 6, within the major histocompatibility complex, which is downregulated in two different mouse models of heritable PKD (N. Aziz, M. Maxwell, B. St.-Jacques, and B.M. Brenner. Mol. Cell. Biol. 13: 1847-1853, 1993). The Ke 6 gene gives rise to two transcripts, Ke 6a and Ke 6b. Ke 6a protein has significant homology to several mammalian and bacterial steroid dehydrogenases. The homology of Ke 6a protein to specific functional domains of the human and rat 11 beta-hydroxysteroid dehydrogenase enzyme (11 beta-HSD), which inactivates glucocorticoids, is substantial. We report here that the Ke 6 gene and the 11 beta-HSD gene are regulated in the same aberrant pattern in the cpk mouse. The strong evidence for a critical role of steroids in cystogenesis leads us to propose that a possible elevation of intrahepatic and intrarenal steroid levels occurs in the cpk mouse as a result of repression of steroid metabolic enzymes, which ultimately leads to development of cysts.
11-beta-Hydroxysteroid Dehydrogenases↗
Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats.
Previous studies of glomerular permselectivity have indicated that both size selectivity and charge selectivity changes play a role in the pathogenesis of proteinuria. In this study, we measured Ficoll sieving coefficients, hemodynamic parameters, and urinary protein excretion rates in the FHH strain of fawn-hooded rats. These animals spontaneously develop systemic and glomerular hypertension, proteinuria, and focal and segmental glomerulosclerosis at a relatively young age. Three groups of FHH rats were studied: two-kidney controls (2K), untreated uninephrectomized rats (CON-NX), and uninephrectomized rats treated with the angiotensin I converting enzyme inhibitor enalapril (ENA-NX). CON-NX rats had higher glomerular transcapillary pressures (delta P) and higher urinary excretion rates of both total protein (UpV) and albumin (UaV) than did 2K rats, whereas treatment with enalapril prevented both glomerular hypertension and the increased proteinuria. Ficoll sieving coefficients were significantly higher in both groups of NX rats compared with 2K rats only for Stokes-Einstein radii (rs) > or = 46 A. Fits of sieving data to pore models showed a small increase in the number of large, nonselective pores in NX, which was not prevented by enalapril treatment. Total clearances of Ficoll with rs = 36 A (the size of albumin) in CON-NX and ENA-NX groups were unchanged compared with 2K animals. In contrast, UaV in CON-NX rats was more than six times that of 2K and ENA-NX rats. Across groups, UpV, UaV, and the ratio (UaV)/(UpV) all correlated strongly with delta P.(ABSTRACT TRUNCATED AT 250 WORDS)
Albuminuria↗
Nephron supply is a major determinant of long-term renal allograft outcome in rats.
The effects of augmenting the nephron supply on indices of allograft injury were assessed in a rat model of "chronic rejection." Orthotopic renal allotransplantation into unine-phrectomized rats was followed by excision (allograft-alone group) or preservation of the remaining native kidney (allograft+native kidney group) such that the total kidney complement was either the allograft alone, or the allograft plus one retained native kidney. After 18 wk, values for GFR (1.85 +/- 0.3 ml/min) and kidney weights (2.3 +/- 0.2 g) in allograft-alone rats were far in excess of corresponding values in the allograft of allograft+native kidney rats (0.88 +/- 0.1 ml/min and 1.1 +/- 0.5 g, respectively). Proteinuria (35 +/- 2 mg/d) and allograft glomerulosclerosis (24 +/- 8%) also characterized allograft-alone but not allograft+native kidney rats, in whom glomerular structure (allograft glomerulosclerosis, 4 +/- 1%; native kidney glomerulosclerosis, 0%) and glomerular functional integrity (proteinuria 7 +/- 0.7 mg/d) were well preserved. Thus, the observed allograft protection derived from the presence of a retained recipient native kidney supports the hypothesis that a single renal allograft contains insufficient nephrons to prevent progressive renal injury, implicating nephron supply as a major determinant of long-term allograft outcome.
Animals↗
HS-142-1, a potent antagonist of natriuretic peptides in vitro and in vivo.
To determine whether HS-142-1 (HS), a potent atrial natriuretic peptide (ANP) receptor antagonist, also inhibits the effects of brain natriuretic peptide (BNP), urodilatin (URO), and C-type natriuretic peptide, in vitro studies were carried out, demonstrating that HS inhibited production of cGMP by rat fetal lung fibroblast cells induced by ANP, BNP, URO, and C-type natriuretic peptide. Acute clearance studies were conducted in euvolemic Munich-Wistar rats under inactin anesthesia to characterize the effects of HS in vivo. In response to ANP, BNP, or URO (4 micrograms/kg priming dose plus 0.5 micrograms/kg per minute for 20 min), urine flow, absolute sodium excretion rates, and fractional sodium excretion exhibited similar increases (four- to fivefold) in vehicle-treated rats; these responses were, however, completely abolished by prior HS treatment. The tendency for GFR to rise during the infusion of natriuretic peptides (NP) was also blocked after HS. By contrast, HS did not block the renal effects of L-arginine, a precursor of nitric oxide, or of furosemide. Furthermore, the inhibition of endogenous NP by HS was associated with small but significant reductions in GFR and absolute and fractional sodium excretion in normal rats under euvolemic but not hydropenic conditions. These studies provide evidence that the observed effects of HS in vivo and in vitro are mediated exclusively by receptors of NP. Together, these data support the view that HS is a highly specific ligand for NP receptors, capable of antagonizing the renal effects not only of exogenous ANP, but also those of BNP and URO.
Animals↗
The etiology of adult hypertension and progressive renal injury: an hypothesis.
We hypothesize that retardation of renal development as occurs in individuals of low birth weight gives rise to increased postnatal risks for systemic and glomerular hypertension as well as enhanced risk of expression of renal disease. This hypothesis draws upon observations suggesting 1) a direct relationship between birth weight and nephron number, 2) an inverse relationship between birth weight and later-life hypertension, and 3) an inverse relationship between nephron number and blood pressure, irrespective of whether nephron number is reduced congenitally or in postnatal life (as from partial renal ablation or acquired renal disease). Additional clinical and epidemiological studies are needed to assess these initial impressions.
Adult↗
Renal mechanisms of salt sensitivity in hypertension.
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Animals↗
TCV 116 prevents progressive renal injury in rats with extensive renal mass ablation.
OBJECTIVE: The objective of this study was to determine the renal protective effects of TCV 116, a novel, non-competitive, angiotensin II type 1 (AT1) receptor antagonist, in rats with 5/6 renal mass ablation. DESIGN: Adult male Wistar rats were subjected to 5/6 nephrectomy and treated continuously with either TCV 116 (group I, n = 8; group III, n = 9) or vehicle (group II, n = 8; group IV, n = 8). The development of elevated systolic blood pressure, 24-h urinary protein excretion, glomerular hemodynamics and glomerular morphology were compared among groups. RESULTS: Systolic blood pressure rapidly reached hypertensive levels in group II, increasing from 175 +/- 8 mmHg after 3 weeks to 221 +/- 15 mmHg after 12 weeks, whereas group I rats remained normotensive (101 +/- 8 to 112 +/- 6 mmHg). Similarly, urinary protein excretion increased from 45 +/- 11 to 104 +/- 18 mg/day in group II, but remained low (6.9 +/- 1 to 19 +/- 4 mg/day) in group I. After 12 weeks, there was an average of 42 +/- 6% glomerulosclerosis in group II, but only 1.6 +/- 0.5% in group I. After 4-6 weeks, a markedly elevated glomerular capillary pressure (62 +/- 1.2 mmHg) was observed in group IV, but the pressure was normal in group III (50 +/- 1.1 mmHg). CONCLUSIONS: These data show that TCV 116 prevents the development of systemic hypertension, glomerular capillary hypertension, proteinuria and glomerulosclerosis in rats with reduced renal mass. We therefore conclude that the renal protection associated with angiotensin I converting enzyme inhibitors and other pharmacologic blockers of the renin-angiotensin system arises chiefly from blockade of AT1 receptor-mediated hemodynamic effects.
Angiotensin Receptor Antagonists↗