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Katherine R Tuttle

Publications and source records attributed to Katherine R Tuttle.

24 records · Page 2Linked to original sources
PubMed2003

Amino acids induce indicators of response to injury in glomerular mesangial cells.

High-protein diets exacerbate glomerular hyperfiltration and the progression of diabetic nephropathy. The purpose of this study was to determine whether amino acids also produce nonhemodynamic injury in the glomerulus. When rat mesangial cells were cultured with an amino acid mixture designed to replicate the composition in plasma after protein feeding, production of mRNA (Northern blot analysis) and/or protein (ELISA or Western blot analysis) for transforming growth factor-beta1 (TGF-beta1), fibronectin, thrombospondin-1 (TSP-1), and collagen IV were enhanced in a manner comparable to a culture with high glucose (30.5 mM). The bioactive portion of total TGF-beta (NRK assay) increased in response to amino acids. The TSP-1 antagonist LSKL peptide reduced bioactive TGF-beta and fibronectin, indicating the dependence of TGF-beta1 activation on TSP-1. DNA synthesis ([3H]thymidine incorporation), an index of cellular proliferation, increased in response to amino acids and was further enhanced by culture with increased levels of both amino acids and glucose. TGF-beta1 and matrix proteins increased when mesangial cells were cultured with excess l-arginine (2.08 mM) alone. Although l-arginine is the precursor of nitric oxide (NO), such responses to amino acids do not appear to be mediated through increased NO production. NO metabolites decreased in the media, and these responses to mixed amino acids or l-arginine were not prevented by NO synthase inhibition. In conclusion, amino acids induce indicators of response to injury in mesangial cells, even when hemodynamic stress is absent. In conditions associated with increased circulating amino acids, such as diabetes and/or a high-protein diet, direct cellular effects could contribute to glomerular injury.

Amino Acids↗
PubMed2003

A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition.

Diabetic nephropathy is one of the most common microvascular complications of diabetes mellitus and the leading cause of end-stage renal disease in developed countries. Current treatment includes glycemic control, blood pressure control (with special emphasis on agents targeting the renin-angiotensin system), a low-protein (0.6 to 0.8 g/kg) diet, and the use of hypolipidemic agents. Although these therapeutic options may slow progression, the burden of disease remains large, and additional therapeutic agents are urgently needed. Ruboxistaurin (LY333531) mesylate is a bisindolylmaleimide that shows a high degree of specificity within the protein kinase C (PKC) gene family for inhibiting PKC beta isoforms. In animal models of diabetes, including the streptozotocin (STZ) rat, Lepr(db)/Lepr(db) mouse, and STZ-Ren 2 rat models, ruboxistaurin normalized glomerular hyperfiltration, decreased urinary albumin excretion, and reduced glomerular transforming growth factor-beta1 and extracellular matrix protein production. As a result, improvements were noted in mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis, and renal function. Other studies using less specific probes of PKC activity also have shown an important role for PKC in the development of diabetic nephropathy and a close relationship to pathways believed to be important in its pathogenesis. Inhibition of PKC beta, a common signaling molecule in diabetes-related renal and vascular injury, holds promise as a novel strategy to improve microvascular and macrovascular outcomes in diabetes. Such therapies are needed to reduce the occurrence of devastating diabetic complications.

Animals↗
PubMed2003

Predictors of ARF after cardiac surgical procedures.

BACKGROUND: In a pilot study, a low preoperative serum ferritin level predicted increased risk for acute renal failure (ARF) after cardiopulmonary bypass. It was hypothesized that this may reflect a decreased ability to bind free iron and defend against oxidative stress. However, the pilot study was performed in a small number of patients (n = 30) operated on by a single surgeon. The purpose of this study was to validate whether the serum ferritin level predicts ARF in a larger sample. METHODS: The present study evaluated 120 patients who underwent procedures performed by eight surgeons at another tertiary referral center. Data were collected prospectively and included patient characteristics, laboratory studies, procedure types, and postoperative course. ARF was defined as a 25% or greater increase in creatinine level 48 hours after surgery. RESULTS: The frequency of ARF was 42%, but no patient required dialysis therapy. Preoperative serum ferritin levels did not differ in the groups with and without ARF (158 +/- 119 and 163 +/- 125 ng/mL, respectively), and rates of ARF did not differ when examined by ferritin quartiles. ARF was more frequent in those who underwent valve surgery (54% versus 35% in patients who did not undergo valve procedures; P = 0.044). The odds ratio for ARF after valve surgery was 2.58 (95% confidence interval, 1.06 to 6.29; P = 0.037), adjusted for longer times of surgery and aortic cross-clamp. Most excess ARF occurred in those who underwent aortic valve replacement (AVR; 62%; P = 0.014 versus nonvalve procedures). CONCLUSION: Low preoperative serum ferritin level was not confirmed to predict ARF after cardiac surgery. Valve procedures, particularly AVR, increased the risk for ARF.

Acute Kidney Injury↗
PubMed2002

Effects of amino acids and glucose on mesangial cell aminopeptidase a and angiotensin receptors.

BACKGROUND: High protein diets and diabetes increase renal renin angiotensin system (RAS) activity, which is associated with glomerular injury. Aminopeptidase A (APA) is a cell surface metalloprotease that degrades angiotensin II (AII) in the mesangium. Mesangial cells (MC) also possess receptors for AII; the type 1 (AT1 receptor) promotes proliferation and fibrosis, while the type 2 (AT2 receptor) opposes these effects. We evaluated whether amino acids and glucose alter expression of APA, AT1 receptor and AT2 receptor in a manner that further augments RAS activity. METHODS: Confluent rat MC were grown in serum-free media for 48 hours prior to exposing to experimental conditions: control (C), high amino acids (HA, mixed amino acid solution added to raise concentrations 5- to 6-fold over C), high glucose (HG 30, mM glucose). Semi-quantitative RT-PCR was used to assess mRNA for APA, AT1 receptor, AT2 receptor, and beta-actin. Values are expressed relative to beta actin. RESULTS: Both HA and HG reduced APA mRNA (HG 1.13 plus minus 0.19, HA 1.12 plus minus 0.16 versus C 1.27 plus minus 0.16 P < 0.05, N = 8). HA increased AT1 receptor mRNA (HA 2.11 plus minus 0.43 versus C 1.14 plus minus 0.28 P < 0.05, N = 8). HG increased AT2 receptor mRNA (HG 1.31 plus minus 0.43 versus C 0.82 plus minus 0.33 P < 0.05, N = 6). CONCLUSIONS: A reduction of APA, in response to high levels of amino acids or glucose, could contribute to increased AII as a result of decreased degradation in MC. The effect of amino acids to increase AT1 receptor expression may further enhance adverse hemodynamic and pro-fibrotic actions of AII. Conversely, glucose increased AT2 receptor expression, which could modulate responses mediated by the AT1 receptor.

Amino Acids↗
PubMed2002

Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes.

Increased dietary protein and circulating amino acids raise glomerular filtration rate (GFR) and pressure. In diabetes, this glomerular hyperfiltration response is augmented. The purpose of this study was to determine whether glucagon mediates the augmented GFR response to amino acids in diabetes and whether the responses to amino acids and glucagon depend on prostaglandins. Patients with type 1 diabetes mellitus (n = 12) and normal control subjects (n = 12) were studied in a series of six experiments, each on different occasions. Baseline GFR was not significantly increased, but filtration fraction was higher in diabetes. In response to amino acid infusion, GFR increased more and filtration fraction was greater among those with diabetes. Their augmented GFR response to amino acids was not inhibited by octreotide or indomethacin. Participants with diabetes also had enhanced GFR and renal plasma flow responses to glucagon infusion, both of which were inhibited by indomethacin. Glomerular hyperfiltration responses induced by amino acids or glucagon occur by divergent pathways in diabetes; only the response to glucagon is prostaglandin dependent.

Adult↗