Protein Handling by the Renal Tubule

Bourdeau, J. E.; Carone, Frank A.

doi:10.1159/000180367

Cited by 65 publications

(18 citation statements)

References 37 publications

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“…[3][4][5][6][7][8] There is negligible contribution of albumin fragments arising from proteolytic activity on the luminal surface of the tubular cells, 9 from extra renal sources, 3 or from contraluminal uptake of albumin with subsequent degradation. 10 Similar rapid lysosomal processing has been demonstrated in vivo associated with the filtration and excretion of dextran sulfate in which the dextran sulfate is completely desulfated but not depolymerized. 11 The ratio of intact to degraded forms of albumin and dextran sulfate has been shown previously to increase in experimental diabetic nephropathy.…”

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confidence: 62%

Albuminuria in Hypertension Is Linked to Altered Lysosomal Activity and TGF-β1 Expression

et al. 2002

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Abstract-Increased intraglomerular pressure is considered a major factor for increased albumin excretion in hypertension.However, other factors should also be considered because recent studies in both humans and rats have demonstrated that proteins undergoing filtration and renal passage are extensively modified by renal cell lysosomal processing; Ͼ95% of albumin is degraded to peptides that are not detected by routine immunochemical assays. Changes in postglomerular lysosomal processing may therefore be responsible for the increased intact albumin excreted in hypertension-related kidney disease. We hypothesize that transforming growth factor-␤, which is known to decrease lysosomal activity, may be upregulated in hypertension and may play a role in increased intact albumin excretion. The aims of this study were to determine the effect that hypertension has on (1) renal cell lysosomal processing of albumin and dextran sulfate, (2) glomerular permeability, and (3) renal transforming growth factor-␤ 1 expression. Spontaneously hypertensive rats and Wistar-Kyoto rats were used at 8, 16, and 24 weeks. We demonstrate that albuminuria in hypertension is linked to an inhibition of lysosomal processing as determined by (1) icroalbuminuria is a recently recognized link between cardiovascular and renal damage in hypertensive diabetic and nondiabetic subjects. 1,2 Many patients with high blood pressure have a renal abnormality. However, the exact relationship between increased glomerular pressure that may be derived from increases in systemic blood pressure, or the specific increases in local intraglomerular pressure without similar changes in systemic pressure and glomerular malfunction have yet to be determined.Although the underlying mechanism responsible for albuminuria in hypertension remains speculative, recent studies suggest that factors other than changes in glomerular permeability should be considered. These studies have demonstrated that albumin excretion in healthy controls is associated with comprehensive degradation (Ͼ95%) by lysosomes in renal cells distal to the glomerular basement membrane (GBM). 3 Previously it was assumed that virtually all proteins filtered by the kidney were excreted intact. In fact Ͻ5% of albumin is excreted intact and detectable by conventional immunochemical assays. The remaining Ͼ95% is degraded and undetectable by routine immunochemical assays. The lysosomal processing of filtered albumin before its excretion has been shown to be an extremely rapid and efficient process. It occurs within minutes and involves lysosomal uptake and exocytosis of peptide products back to the tubular lumen by renal cells distal to the GBM. [3][4][5][6][7][8] There is negligible contribution of albumin fragments arising from proteolytic activity on the luminal surface of the tubular cells, 9 from extra renal sources, 3 or from contraluminal uptake of albumin with subsequent degradation. 10 Similar rapid lysosomal processing has been demonstrated in vivo associated with the filtration and excretion of de...

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confidence: 62%

Albuminuria in Hypertension Is Linked to Altered Lysosomal Activity and TGF-β1 Expression

et al. 2002

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“…Contraluminal uptake of proteins leading to a potential alternative route by which proteins could appear in urine has been demonstrated to be negligible. 29 The internalization of filtered protein, such as 125 I-labeled albumin, by the apical side of the proximal tubular cell and then transport to the lysosomes has been shown by autoradiography. 30 The fact that protein fragments resulting from exocytosis of lysosomal degradation was not recognized until recently is not surprising as microscopical techniques may not detect such rapid cellular processing of peptide fragments.…”

Section: Discussionmentioning

confidence: 99%

Glomerular Permselectivity Factors Are Not Responsible for the Increase in Fractional Clearance of Albumin in Rat Glomerulonephritis

Greive

Nikolic‐Paterson

Guimarães

et al. 2001

The American Journal of Pathology

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The increased fractional clearance of albumin in nephrotic states has long been attributed to glomerular permselectivity dysfunction. Using radiolabeled rat serum albumin, transferrin, IgG, and polydisperse Ficoll, this study investigated the changes in their in vivo fractional clearance in puromycin aminonucleoside nephrosis and anti-glomerular basement membrane glomerulonephritis. In control rats the lack of charge selectivity was confirmed by the demonstration that carboxymethyl Ficoll (valence ϳ؊39) had the same fractional clearance as uncharged Ficoll. Both diseases exhibited similar effects on fractional clearance measurements suggesting an underlying common mechanism. In disease, there was good agreement between the fractional clearance of proteins determined by radioactivity as compared to those determined by radioimmunoassay. A small increase in the fractional clearance for IgG was evident in disease as compared to controls, which mirrored the change in the equivalent size Ficoll, suggesting that the increase is because of the development of a small proportion of large pores in the glomerular capillary wall. There was no increase, however, in the fractional clearance of Ficoll of equivalent size to albumin in either disease, yet the fractional clearance of the albumin increased by 12 to 14 times as determined by radioactivity and 4500 to 6600 times as determined by radioimmunoassay. This study demonstrates that glomerulonephritis is not a disease associated with changes in glomerular permeability to albumin but is because of alterations in albumin processing by cells distal to the glomerular basement membrane. It is also apparent that approaches to glomerular pathology and proteinuria as risk factors in renal disease must be reassessed. (Am J Pathol 2001, 159:1159 -1170)

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“…Failure to do so would, in the absence of endocytic mechanisms for peptides (as distinct from proteins, e.g. insulin [66]), lead to their passage into the urine after some degree of concentration. The nutritional losses would appear to be trivial, amounting in the human to only a few milligrams of peptide.…”

Section: What Is the Physiological Role Of The Renal Brush Border Pepmentioning

confidence: 99%

Role of endopeptidase‐24.11 in the inactivation of atrial natriuretic peptide

1988

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The circulating form of atria1 natriuretic factor is a 28-residue peptide containing a 17-residue disulphide-linked ring. It has important actions on the kidney, largely on its haemodynamics, and at other sites including the adrenal cortex and CNS. It has a short half-life in vivo and is rapidly inactivated when incubated with kidney microvillar membranes. Of the battery of peptidases present in that membrane, only one, endopeptidase-24.11, is responsible for initiating the attack, and this commences with hydrolysis of the Cys'-PheS bond within the ring. Hydrolysis at this and other points has been shown to inactivate the peptide and this information has pointed the way to the synthesis of resistant analogues.Atria1 natriuretic peptide; Membrane peptidase; Neuropeptide; Endopeptidase-24.11 DISCOVERY OF ATRIAL NATRIURETIC FACTORAtria1 natriuretic factor (ANF) comprises a family of peptides with powerful natriuretic, diuretic and hypotensive activities which are present in storage granules of atrial muscle. The existence of these granules and their resemblance to secretory granules of other cells were reported more than 20 years ago [1,2] Abbreviations: ANF, atria1 natriuretic factor; ANP, atrial natriuretic peptide (l-28) the prefixes h and r indicating human and rat; could be affected by changes in the intake of water and sodium [3] and that injections of extracts of atria or granules promoted diuresis and natriuresis [4] and by 1983 it was becoming clear that these activities resided in a group of related peptides (for review and nomenclature see [S]). Several low-M, peptides have been isolated from rat atria, e.g. atriopeptins I, II and III and cu-rat atria1 natriuretic peptide (cu-rANP), all of which possess a disulphide-linked loop of 17 amino acid residues, with short N-and C-terminal extensions. However, the major circulating form of ANF in the rat appears to be the 28-residue peptide [6,7] which is derived from a high-M,, 152-residue precursor, rat pre-pro ANP (see [5]). Human atria also release a 28-amino acid peptide @-human atrial natriuretic peptide, a-hANP; [8]; fig.1) which differs from a-rANP by only one residue, Met" for Ilei* [9]. REGULATION OF RELEASE OF ANPSeveral factors have been found to stimulate

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Protein Handling by the Renal Tubule

Cited by 65 publications

References 37 publications

Albuminuria in Hypertension Is Linked to Altered Lysosomal Activity and TGF-β1 Expression

Albuminuria in Hypertension Is Linked to Altered Lysosomal Activity and TGF-β1 Expression

Glomerular Permselectivity Factors Are Not Responsible for the Increase in Fractional Clearance of Albumin in Rat Glomerulonephritis

Role of endopeptidase‐24.11 in the inactivation of atrial natriuretic peptide

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