Chronic endothelin-1 infusion elevates glomerular sieving coefficient and proximal tubular albumin reuptake in the rat (original) (raw)
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Hypertension, 2010
Endothelin-1 (ET-1) is a potent vasoactive peptide implicated in the pathogenesis of hypertension and renal disease. The aim of the current study was to test the hypotheses that ET-1 increases albumin permeability of glomeruli isolated from normal rats and that chronic ET-1 infusion will increase glomerular permeability and inflammation independent of blood pressure. Glomerular permeability to albumin (P alb ) was determined from the change in glomerular volume induced by exposing isolated glomeruli to oncotic gradients. Incubation of glomeruli taken from normal rats with ET-1 at a concentration that did not produce direct glomerular contraction (1 nM) significantly increased P alb , reaching a maximum after 4 hrs. Chronic ET-1 infusion for 2 weeks in Sprague-Dawley rats significantly increased P alb and nephrin excretion rate; effects that were attenuated in rats given an ET A receptor antagonist (ABT-627, 5 mg/kg/day). Urinary protein and albumin excretion and mean arterial pressure (telemetry) were not changed by ET-1 infusion. Acute incubation of glomeruli isolated from ET-1-infused rats with the selective ET A antagonist significantly reduced P alb ; an effect not observed with acute treatment with a selective ET B antagonist. Chronic ET-1 infusion increased glomerular and plasma sICAM-1 (soluble inter-cellular adhesion molecule-1) and MCP-1 (monocyte chemoattractant protein-1) and elevated the number of macrophages and lymphocytes in renal cortices (ED-1 and CD3 positive staining, respectively). These effects were all attenuated in rats given an ET A selective antagonist. These data support the hypothesis that ET-1 directly increases glomerular permeability to albumin and renal inflammation via ET A receptor activation independent of changes in arterial pressure.
Mechanisms of glomerular albumin filtration and tubular reabsorption
International journal of nephrology, 2012
Albumin is filtered through the glomerulus with a sieving coefficient of 0.00062, which results in approximately 3.3 g of albumin filtered daily in human kidneys. The proximal convoluted tubule reabsorbs 71%, the loop of Henle and distal tubule 23%, and collecting duct 3% of the glomerular filtered albumin, thus indicating that the kidney plays an important role in protein metabolism. Dysfunction of albumin reabsorption in the proximal tubules, due to reduced megalin expression, may explain the microalbuminuria in early-stage diabetes. Meanwhile, massive nonselective proteinuria is ascribed to various disorders of the glomerular filtration barrier, including podocyte detachment, glomerular basement membrane rupture, and slit diaphragm dysfunction in focal segmental glomerulosclerosis, membranous nephropathy, and other glomerulonephritis. Selective albuminuria associated with foot process effacement and tight junction-like slit alteration is observed in the patients with minimal-chan...
Journal of Clinical Investigation, 1993
Microalbuminuria (26-250 mg/d) is considered to be an indicator of incipient diabetic nephropathy in humans in insulin-dependent diabetes (IDD). However, before microalbuminuria is observed, glomerular alterations, such as glycosylation of the glomerular basement membrane and glomerular hyperfiltration, in IDD may result in increased filtration of albumin before any observed increase in albumin excretion. Glomerular and tubular albumin kinetics were examined in streptozotocin (65 mg/kg body wt, i.v.) diabetic, Munich-Wistar rats at 7-10 (untreated) and 50-70 d (poorly controlled with small doses of insulin) after the onset of diabetes and compared with nondiabetic controls. Additional rats in each condition received acute lysine treatment to prevent tubular protein reabsorption. Urinary albumin excretion and nonvascular albumin distribution volumes were measured in the renal cortex and compared with morphometric measurements of interstitial space and the proximal tubule to assess intracellular uptake of albumin in the proximal tubule. Urinary albumin excretion under anesthesia was not different in 7-10-d IDD versus controls (19±3 vs. 20±3 gg/min) but increased in the 50-70-d IDD (118±13 fig/ min, P < 0.05). Lysine treatment resulted in increased albumin excretion compared with respective nontreatment in 7-10-d IDD (67±10 ,ug/min, P < 0.05) but not in controls (30±6 ,gg/min) or in 50-70-d IDD (126±11 tg/min). Glomerular filtration rate was increased both in 7-10-d IDD (2.7±0.1 ml/ min, P < 0.05) and in 50-70-d IDD (2.6±0.1 ml/min, P < 0.05) compared with control (2.2±0.1 ml/min). Calculated urinary space albumin concentrations increased early in IDD with 2.5±0.4 mg% in 7-10-d IDD and 4.9±0.6 mg% in 50-70-d IDD compared with control (1.4±0.3 mg%). The increase in filtration of albumin is in excess of that attributable to hyperfiltration before increased albumin excretion early in diabetes. In 50-70-d IDD, absolute tubular reabsorption of albumin is decreased, correlating to the decrease in brush border height of the proximal tubule. (J. Clin. Invest. 1993. 92:686-694.) Key words: transcapillary albumin escape rate * urinary albumin
Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats
Journal of Clinical Investigation, 1971
concentration of serum albumin in proximal tubule fluid of normal rats and animals with aminonucleoside nephrosis was studied using renal micropuncture techniques. Albumin was quantitated by an ultramicrodisc electrophoresis method capable of measuring 3 X 10'" g of albumin, in 10 nl volumes. With this sensitivity., only small samples of tubule fluid were required for analysis. Collectifn times could be kept short, therefore decreasing the opportunity for sample contamination with extraneous serum albumin. The measured mean concentration of albumin in proximal tubule fluid (1 mg/100 ml in females and 0.7 mg/ 100 ml in males) was somewhat lower than values reported by others, but even these values are apt to have been artifactually high as a result of animal preparation and trace contamination of samples during micropuncture. Rats injected with aminonucleoside of puromycin 4 days earlier, showed a significant increase in tubulefluid albumin concentration coincident with a fall in serum albumin concentration and a 43-fold increase in urine albumin concentration. Tubular absorption of albumin was small relative to that of water. Although albumin filtration was significantly increased over that in normal animals, the glomerular basement membrane still served as a highly efficient barrier to albumin transfer.
Clinical and experimental pharmacology & physiology, 2017
Tubular epithelial cells take up and degrade plasma albumin filtered by the glomerulus. Tubular damage resulting in reduced albumin uptake or degradation has been suggested as one mechanism contributing to albuminuria in kidney disease. This study investigated whether albumin uptake or degradation is altered in acute and chronic glomerular disease. Mouse models of acute glomerular injury (anti-GBM disease and LPS-induced albuminuria) and chronic disease (streptozotocin-induced diabetes and db/db mice) were examined. Mice were injected intravenously with Alexa-albumin plus DQ-albumin and euthanized 20 minutes later. Tubular uptake of albumin (Alexa-albumin) and albumin degradation (Dye Quenched (DQ)-albumin) was assessed in tissue sections via confocal microscopy. Tubular uptake of Alexa-albumin in the models of diabetic nephropathy was not different to normal mice. However, the fluorescence signal resulting from degradation of DQ-albumin was significantly reduced in db/db mice, and ...
Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys
American journal of physiology. Renal physiology, 2003
The size and charge-selective properties of the glomerular barrier are partly controversial. Glomerular sieving coefficients (theta) for proteins have rarely been determined noninvasively before in vivo. Therefore, theta was assessed vs. glomerular filtration rate (GFR; (51)Cr-EDTA clearance) in intact rats for radiolabeled myoglobin, kappa-dimer, neutral horseradish peroxidase (nHRP), neutral human serum albumin (nHSA), and native albumin (HSA). To obtain theta, glomerular tracer clearance, assessed from the 7- to 8-min kidney uptake of protein, was divided by the GFR. The data were fitted with a two-pore model of glomerular permeability, where the small-pore radius was 37.35 +/- 1.11 (SE) A, and the "unrestricted pore area over diffusion path length" (A(0)/DeltaX) 1.84 +/- 0.43 x 10(6) cm. Although seemingly horizontal for nHRP and nHSA, the log theta vs. GFR curves showed slightly negative slopes for the proteins investigated in the GFR interval of 2-4.5 ml/min. Strong ...