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Biomedical subjects

L Lee Hamm

Publications and source records attributed to L Lee Hamm.

At least 19 recordsLinked to original sources
PubMed2007

Molecular mechanisms of renal ammonia transport.

Acid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH(3) diffusion and NH(4)(+) trapping has given way to a model postulating that a variety of proteins specifically transport NH(3) and NH(4)(+) and that this transport is critical for normal ammonia metabolism. Many of these proteins transport primarily H(+) or K(+) but also transport NH(4)(+). Nonerythroid Rh glycoproteins transport ammonia and may represent critical facilitators of ammonia transport in the kidney. This review discusses the underlying aspects of renal ammonia transport as well as specific proteins with important roles in renal ammonia transport.

Ammonia↗
PubMed2005

Growth factors stimulate kidney proximal tubule cell migration independent of augmented tyrosine phosphorylation of focal adhesion kinase.

Migration of human proximal tubule cells (HKC-5) was stimulated by epidermal growth factor (EGF), hepatocyte growth factor (HGF), and insulin-like growth factor-1 (IGF-1). Integrin signaling via phosphorylation of focal adhesion kinase (FAK) appears to play a central role in cell migration. Once stimulated, FAK undergoes autophosphorylation at tyrosine (Y) 397, followed by phosphorylation of several sites including Y576/Y577 which increases FAK's kinase activity, as well as at Y407, Y861, and Y925. EGF, HGF, and IGF-1 stimulate FAK phosphorylation in various cells. We showed that endothelin stimulated phosphorylation of Y397 in fibroblasts but not HKC-5 cells. After EGF stimulation, HKC-5 cells showed no change in tyrosine phosphorylation at FAK Y397, 407, 576, 861, or 925. Similarly, HGF and IGF-1 did not stimulate the phosphorylation of FAK Y397 in HKC-5 cells. Further, after inhibition of FAK expression by siRNA, cell migration was similar to cells treated with non-target siRNA and responded to EGF with increased migration. Thus, in proximal tubule cells, stimulation of cell migration by growth factors was independent of augmented FAK tyrosine phosphorylation.

3T3 Cells↗
PubMed2005

The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension.

BACKGROUND: The cytochrome P450 (CYP) epoxygenase pathway produces arachidonic acid metabolites that are vasoactive, that affect renal sodium handling, and that have been proposed to play a mechanistic role in hypertension. Multiple single nucleotide polymorphisms (SNP) in CYP2C8, 2C9, 2J2 and soluble epoxide hydrolase (sEH) have been identified, many of which have altered functional activity in vitro. We performed a case-control study to determine the prevalence of epoxygenase-related SNP in African American individuals and to evaluate whether these SNP are associated with increased risk of hypertension. METHODS: Normotensive African American individuals (N = 107) and African American patients with hypertension (N = 108) were recruited. DNA was extracted from a venous blood sample and genotyped for CYP2C8*2,*3, CYP2C9*2-*5,*8,*11, CYP2J2 *2-*7, L50L, R49S, V113M, N124S, sEH R287Q, and sEH 403Rins variant alleles by allelic discrimination using real-time polymerase chain reaction. Genotype and allele frequencies were calculated and associations with hypertension were estimated using unconditional logistic regression, adjusting for age and sex. RESULTS: No association was found between any of the variant alleles and hypertension. We did find that only the CYP2C8*3and CYP2C9*2 alleles were in strong linkage disequilibrium in both the hypertensive and healthy African American groups, a finding that was reported previously in healthy individuals of white ethnicity. CONCLUSIONS: These results suggest that these epoxygenase-related SNP are not associated with increased risk of hypertension in the African American population. There was significant linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles that was not associated with hypertension.

Adult↗
PubMed2005

Prevalence of decreased kidney function in Chinese adults aged 35 to 74 years.

BACKGROUND: Chronic kidney disease (CKD) is a major public health burden in Western countries but little is known about its impact in developing countries. We estimated the prevalence and absolute burden of CKD in the general adult population in China. METHODS: A cross-sectional survey was conducted in a nationally representative sample of 15,540 Chinese adults aged 35 to 74 years in 2000 and 2001. Serum creatinine was measured using the modified kinetic Jaffe reaction method at a central laboratory calibrated to the Cleveland Clinic Foundation laboratory. Glomerular filtration rate (GFR) was estimated using the simplified equation developed by the Modification of Diet in Renal Disease study. CKD was defined as an estimated GFR <60 mL/min/1.73m2. RESULTS: Overall, the age-standardized prevalences of GFR 60 to 89, 30 to 59, and <30 mL/min/1.73m2 were 39.4%, 2.4%, and 0.14%, respectively, in Chinese adults aged 35 to 74 years. The overall prevalence of CKD (GFR <60 mL/min/1.73m2) was 2.53%, representing 11,966,653 persons (1.31% or 3,185,330 men and 3.82% or 8,781,323 women). The age-specific prevalence of CKD was 0.71%, 1.69%, 3.91%, and 8.14% among persons 35 to 44, 45 to 54, 55 to 64, and 65 to 74 years old, respectively. The age-standardized prevalence of CKD was similar in urban (2.60%) and rural (2.52%) residents but was higher in south China (3.05%) than in north China (1.78%) residents. CONCLUSION: Although the prevalence of CKD in China was relatively low, the population absolute burden is substantial. These data warrant a national program aimed at detection, prevention, and treatment of CKD in China.

Adult↗
PubMed2004

Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study.

Uric acid has been proposed as an important risk factor in the development of primary hypertension in humans. However, limited information is available linking childhood uric acid levels and blood pressure levels in adulthood. This study examined 334 whites and 243 blacks enrolled in the Bogalusa Heart Study as children aged 5 to 17 years and as adults aged 18 to 35 years. The average follow-up period was 12 years. Childhood uric acid was significantly correlated with childhood and adult blood pressure, both systolic and diastolic. In a multivariate regression analysis, adjusting for age, sex, race, childhood body mass index, childhood uric acid levels, and change in levels of uric acid were significant predictors of adult diastolic blood pressure, whereas change in uric acid was a significant predictor of adult systolic blood pressures. In conclusion, elevated childhood serum uric acid levels are associated with increased blood pressure beginning in childhood and higher blood pressure levels that persist into adulthood, in males and females, whites and blacks, suggesting that early elevations in serum uric acid levels may play a key role in the development of human hypertension.

Adolescent↗
PubMed2004

Characteristics of renal Rhbg as an NH4(+) transporter.

Rhbg is one of two recently cloned nonerythroid glycoproteins belonging to the Rh antigen family. Rhbg is expressed in basolateral membranes of intercalated cells of the kidney cortical collecting duct and some other cell types of the distal nephron and may function as NH(4)(+) transporters. The aim of this study was to characterize the role of Rhbg in transporting NH(4)(+). To do so, we expressed Rhbg in Xenopus laevis oocytes. Two-electrode voltage-clamp and H(+)-selective microlectrodes were used to measure NH(4)(+) currents, current-voltage plots, and intracellular pH (pH(i)). In oocytes expressing Rhbg, 5 mM NH(4)(+) induced an inward current of 93 +/- 7.7 nA (n = 20) that was significantly larger than that in control oocytes of -29 +/- 7.1 nA (P < 0.005). Whole cell conductance, at all tested potentials (-60 to +60 mV), was significantly more in oocytes expressing Rhbg compared with H(2)O-injected oocytes. In Rhbg oocytes, 5 mM NH(4)(+) depolarized the oocyte by 28 +/- 3.6 mV and decreased pH(i) by 0.30 +/- 0.04 at a rate of -20 +/- 2.5 x 10(-4) pH/s. In control oocytes, 5 mM NH(4)(+) depolarized V(m) by only 20 +/- 5.8 mV and pH(i) decreased by 0.07 +/- 0.01 at a rate of -2.7 +/- 0.6 x 10(-4) pH/s. Raising bath [NH(4)(+)] in increments from 1 to 20 mM elicited a proportionally larger decrease in pH(i) (DeltapH(i)), larger depolarization (DeltaV(m)), and a faster rate of pH(i) decrease. Bathing Rhbg oocytes in 20 mM NH(4)(+) induced an inward current of 140 +/- 7 nA that was not significantly different from 178 +/- 23 nA induced in H(2)O-injected (control) oocytes. The rate of pH(i) decrease induced by increasing external [NH(4)(+)] was significantly faster in Rhbg than in H(2)O-injected oocytes at all external NH(4)(+) concentrations. In oocytes expressing Rhbg, net NH(4)(+) influx (estimated from NH(4)(+)-induced H(+) influx) as a function of external [NH(4)(+)] saturated at higher [NH(4)(+)] with a V(max) of approximately 30.8 and an apparent K(m) of 2.3 mM (R(2) = 0.99). These data strongly suggest that Rhbg is a specific electrogenic transporter of NH(4)(+).

Animals↗
PubMed2004

Enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats.

Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II-infused rats. Kidneys from sham (n=9) and Ang II-infused (80 ng/kg per minute, 13 days, n=10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181+/-4 versus 115+/-5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II-infused rats compared with sham (0.1+/-0.1 versus 1.0+/-0.1 relative ratio) but increased in distal nephron segments (6.4+/-1.4 versus 1.0+/-0.1 cortex; 2.5+/-0.3 versus 1.0+/-0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II-infused rats compared with that of sham (0.4+/-0.2 versus 1.0+/-0.4) rats but higher in the kidney medulla (1.2+/-0.4 versus 1.0+/-0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang II-dependent hypertension.

Angiotensin II↗
PubMed2004

The metabolic syndrome and chronic kidney disease in U.S. adults.

BACKGROUND: The metabolic syndrome is a common risk factor for cardiovascular disease. OBJECTIVE: To examine the association between the metabolic syndrome and risk for chronic kidney disease and microalbuminuria. DESIGN: Cross-sectional study. SETTING: The Third National Health and Nutrition Examination Survey. PATIENTS: Participants 20 years of age or older were studied in the chronic kidney disease (n = 6217) and microalbuminuria (n = 6125) analyses. MEASUREMENTS: The metabolic syndrome was defined as the presence of 3 or more of the following risk factors: elevated blood pressure, low high-density lipoprotein cholesterol level, high triglyceride level, elevated glucose level, and abdominal obesity. Chronic kidney disease was defined as a glomerular filtration rate less than 60 mL/min per 1.73 m2, and microalbuminuria was defined as a urinary albumin-creatinine ratio of 30 to 300 mg/g. RESULTS: The multivariate-adjusted odds ratios of chronic kidney disease and microalbuminuria in participants with the metabolic syndrome compared with participants without the metabolic syndrome were 2.60 (95% CI, 1.68 to 4.03) and 1.89 (CI, 1.34 to 2.67), respectively. Compared with participants with 0 or 1 component of the metabolic syndrome, participants with 2, 3, 4, and 5 components of chronic kidney disease had multivariate-adjusted odds ratios of 2.21 (CI, 1.16 to 4.24), 3.38 (CI, 1.48 to 7.69), 4.23 (CI, 2.06 to 8.63), and 5.85 (CI, 3.11 to 11.0), respectively. The corresponding multivariate-adjusted odds ratios of microalbuminuria for participants with 3, 4, and 5 components were 1.62 (CI, 1.10 to 2.38), 2.45 (CI, 1.55 to 3.85), and 3.19 (CI, 1.96 to 5.19), respectively. CONCLUSIONS: These findings suggest that the metabolic syndrome might be an important factor in the cause of chronic kidney disease.

Adult↗
PubMed2004

The prevalence of nontraditional risk factors for coronary heart disease in patients with chronic kidney disease.

BACKGROUND: Risk for coronary heart disease is high among patients with chronic kidney disease. OBJECTIVE: To compare the prevalence of low apolipoprotein A1 levels and elevated apolipoprotein B, plasma fibrinogen, lipoprotein(a), homocysteine, and C-reactive protein levels by estimated glomerular filtration rate (GFR). DESIGN: Cross-sectional study. SETTING: Third National Health and Nutrition Examination survey. PARTICIPANTS: 12 547, 3180, and 744 persons with estimated GFRs of at least 90, 60 to 89, or less than 60 mL/min per 1.73 m2, respectively, who were at least 18 years of age. MEASUREMENTS: Chronic kidney disease was defined as an estimated GFR of less than 60 mL/min per 1.73 m2 based on the abbreviated Modification of Diet in Renal Disease formula. RESULTS: After standardization for age, race or ethnicity, and sex, lower estimated GFR (> or =90, 60 to 89, or <60 mL/min per 1.73 m2) was associated with lower average levels of apolipoprotein A1 (1.44, 1.43, and 1.35 g/L) and higher levels of apolipoprotein B (1.03, 1.06, and 1.08 g/L), plasma fibrinogen (8.43, 8.44, and 9.53 micromol/L), homocysteine (8.5, 10.0, and 13.2 micromol/L), and C-reactive protein (3.0, 2.9, and 3.9 mg/L) (P < 0.05 for all values). The multivariate-adjusted odds ratios of an apolipoprotein A1 level of less than 1.2 g/L, a serum lipoprotein(a) level of at least 1.61 micromol/L (> or =45.3 mg/dL), a plasma fibrinogen level of at least 10.35 micromol/L, a serum homocysteine level of at least 15 micromol/L, and a C-reactive protein level of at least 10.0 mg/L for participants with chronic kidney disease compared with those with a GFR of at least 90 mL/min per 1.73 m2 or greater were 1.92 (95% CI, 1.02 to 3.63), 1.82 (CI, 1.06 to 3.13), 1.74 (CI, 1.35 to 2.24), 8.23 (CI, 5.00 to 13.6), and 1.93 (CI, 1.33 to 2.81), respectively. CONCLUSIONS: Levels of apolipoprotein A1 are decreased and levels of homocysteine, lipoprotein(a), fibrinogen, and C-reactive protein are increased among patients with chronic kidney disease.

Adult↗
PubMed2004

Association between inflammation and insulin resistance in U.S. nondiabetic adults: results from the Third National Health and Nutrition Examination Survey.

Clinical and epidemiological data indicate that inflammation may be associated with insulin resistance. We examined the association between inflammatory markers, such as ferritin, uric acid, white cell counts, fibrinogen, and C-reactive protein, and insulin resistance among 5,959 adults, aged > or =20 years and without diabetes (fasting glucose <126 mg/dl and not taking diabetes medication), who participated in the Third National Health and Nutrition Examination Survey. Insulin resistance was calculated using the homeostasis model assessment (HOMA). Levels of ferritin, uric acid, white cell counts, fibrinogen, and C-reactive protein were significantly higher in individuals with a higher HOMA of insulin resistance (HOMA-IR). After adjustment for age, sex, race, education, physical inactivity, current and former smoking, alcohol intake, use of nonsteroidal anti-inflammatory drugs, systolic blood pressure, BMI, waist circumference, serum total cholesterol, and triglycerides, a 1-SD higher ferritin (126.1 ng/ml), uric acid (1.4 mg/dl), white blood cell count (2.2 x 10(9)/l), and fibrinogen (80.6 mg/dl) was associated with a 0.10 (95% CI 0.03-0.17, P=0.004), 0.16 (0.08-0.24, P <0.001), 0.16 (0.09-0.22, P <0.001), and 0.12 (0.05-0.18, P=0.001) higher HOMA-IR, respectively. Clinically elevated C-reactive protein (> or =1.0 mg/dl) was associated with a 0.63 (0.23-1.04, P=0.003) higher HOMA-IR. These findings indicate that elevated levels of inflammatory markers are positively and independently associated with insulin resistance. Further studies should examine the potential causal effect of inflammation on insulin resistance.

Adult↗
PubMed2003

Non-erythroid Rh glycoproteins: a putative new family of mammalian ammonium transporters.

The Rhesus (Rh) glycoproteins, originally described in human blood cells, are mostly recognized for their immunogenic characteristics and importance in pregnancy. The Rh proteins in the red blood cell are expressed as an "Rh complex" made up of one D-subunit, one CE-subunit and two Rh-associated glycoprotein (RhAG) subunits. In addition to its antigenic property, the Rh complex is thought to contribute to membrane stability and structure of red blood cells. The exact function is yet to be determined. Recently, two non-erythroid Rh glycoproteins were cloned from mice (Rhcg and Rhbg) and humans (RhCG and RhBG). RhCG is expressed at the membrane surface alone with no apparent need for heteromeric interaction with other glycoproteins. It is more similar to RhAG than to Rh CE/D, occurs late in development and is expressed abundantly and broadly in kidney and testis. In the kidney RhCG is localized to the apical cell membrane of the collecting duct. Rhbg and its human analog (RhBG) are expressed mainly in liver, skin and the kidney tubules. In the kidney collecting duct, Rhbg is localized to the basolateral membrane. Based on structural similarities to the methylammonium and ammonium permease/ammonium (MEP/Amt) transporters in yeast and their sequence homology, these proteins probably function as NH(4)(+) transporters. An initial study has indicated that RhAG or RhCG promote efflux of NH(4)(+), whereas another study has suggested that RhAG functions as an NH(4)(+)-H(+) exchanger. Evidence for such a function is still circumstantial and data indicating that Rh proteins function as NH(4)(+) transporters are indirect.

Animals↗
PubMed2003

Insulin resistance and risk of chronic kidney disease in nondiabetic US adults.

This study examined the relationship of fasting serum glucose, insulin, C-peptide, glycosylated hemoglobin A (HbA1c), and Homeostasis Model Assessment (HOMA)-insulin resistance to risk of chronic kidney disease (CKD) among 6453 persons without diabetes (fasting glucose <126 mg/dl and not taking diabetes medication) who participated in the Third National Health and Nutrition Examination Survey and were aged 20 yr or older. CKD was defined as an estimated GFR <60 ml/min per 1.73 m(2). The prevalence of CKD was significantly and progressively higher with increasing levels of serum insulin, C-peptide, HbA1c, and HOMA-insulin resistance. After adjustment for potential confounding variables, the odds ratio of CKD for the highest compared with the lowest quartile was 4.03 (95% confidence interval [CI], 1.81 to 8.95; P = 0.001), 11.4 (95% CI, 4.07 to 32.1; P < 0.001), 2.67 (95% CI, 1.31 to 5.46; P = 0.002), and 2.65 (95% CI, 1.25 to 5.62; P = 0.008) for serum insulin, C-peptide, HbA1c levels, and HOMA-insulin resistance, respectively. For a one SD higher level of serum insulin (7.14 micro U/ml), C-peptide (0.45 Deltamol/ml), HbA1c (0.52%), and HOMA-insulin resistance (1.93), the odds ratio (95% CI) of CKD was 1.35 (1.16 to 1.57), 2.78 (2.25 to 3.42), 1.69 (1.28 to 2.23), and 1.30 (1.13 to 1.50), respectively. These findings combined with knowledge from previous studies suggest that the insulin resistance and concomitant hyperinsulinemia are presented in CKD patients without clinical diabetes. Further studies into the causality between insulin resistance and CKD are warranted.

Blood Glucose↗
PubMed2003

The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods.

Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.

Adult↗
PubMed2003

Bone buffering of acid and base in humans.

The sources and rates of metabolic acid production in relation to renal net acid excretion and thus acid balance in humans have remained controversial. The techniques and possible errors in these measurements are reviewed, as is the relationship of charge balance to acid balance. The results demonstrate that when acid production is experimentally increased among healthy subjects, renal net acid excretion does not increase as much as acid production so that acid balances become positive. These positive imbalances are accompanied by equivalently negative charge balances that are the result of bone buffering of retained H+ and loss of bone Ca2+ into the urine. The data also demonstrate that when acid production is experimentally reduced during the administration of KHCO3, renal net acid excretion does not decrease as much as the decrease in acid production so that acid balances become negative, or, in opposite terms, there are equivalently positive HCO3- balances. Equivalently positive K+ and Ca2+ balances, and thus positive charge balances, accompany these negative acid imbalances. Similarly, positive Na+ balances, and thus positive charge balances, accompany these negative acid balances during the administration of NaHCO3. These charge balances are likely the result of the adsorption of HCO3- onto the crystal surfaces of bone mineral. There do not appear to be significant errors in the measurements.

Acid-Base Equilibrium↗