High-Glucose Media Enhance the Responsiveness of Tubular Cells to Growth Promoters: Effect on Lysosomal Cathepsins and Protein Degradation

Schenk, Oliver; Li, Hong; Šebeková, Katarı́na; Vamvakas, Spiros; Heidland, A.

doi:10.1159/000057378

Cited by 16 publications

(12 citation statements)

References 28 publications

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“…11 These results may be linked to changes in transforming growth factor-␤ (TGF-␤) expression, which is upregulated in diabetes and other kidney disease states 12 and may be upregulated in hypertension as a result of increased stretching forces [13][14][15] brought about by the hypertensive state. Recent studies have shown that lysosomal activity may be affected by increased TGF-␤ levels, 16 and its role in albuminuria induction may be further supported by the fact that ACE inhibitors and decreasing albuminuria are correlated with decreased TGF-␤ levels, 17 which leads to the hypothesis to be tested in this study.…”

mentioning

confidence: 71%

“…A possible linkage factor is the role of TGF-␤. This growth factor is known to decrease lysosomal enzyme activities, 16 with increased production of TGF-␤ by mesangial cells when subjected to stretching forces brought about by high intraglomerular pressures. [13][14][15] Our results suggest that TGF-␤ production in hypertension may be playing a role in albuminuria through this mechanism, with results showing decreased lysosomal activity with an upregulation of TGF-␤, resulting in increased intact albuminuria irrespective of changes in glomerular permeability and net albumin excretion.…”

Section: Discussionmentioning

confidence: 99%

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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: 71%

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

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“…Thus, the increased albumin excretion rate may be due to either a glomerular charge-selectivity defect or to decreased tubular catabolism. Recent studies suggest that an increased glomerular pressure may increase albumin excretion rate by affecting glomerular cell metabolism: stretching of mesangial cells by increased pressure (38 -40) increases the production of TGF-␤, which may impair the lysosomal enzyme activity in tubular cells (41,42). This leads to increased urinary albumin excretion independently of an altered glomerular permselectivity, as shown in a model of hypertension-induced albuminuria (42).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Weight Loss on Renal Function in Patients with Severe Obesity

Chagnac¹,

Weinstein²,

Herman³

et al. 2003

Journal of the American Society of Nephrology

476

341

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Abstract. Severe obesity is associated with increased renal plasma flow (RPF) and glomerular filtration rate (GFR). The aim of the present study was to examine whether weight loss may reverse glomerular dysfunction in obese subjects without overt renal disease. Renal glomerular function was studied in eight subjects with severe obesity (body mass index [BMI] 48.0 Ϯ 2.4) before and after weight loss. Nine healthy subjects served as controls. GFR and RPF were determined by measuring inulin and PAH clearance. In the obese group, GFR (145 Ϯ 14 ml/min) and RPF (803 Ϯ 39 ml/min) exceeded the control value by 61% (90 Ϯ 5 ml/min, P ϭ 0.001) and 32% (610 Ϯ 41 ml/min, P Ͻ 0.005), respectively. Consequently, filtration fraction was increased.Mean arterial pressure, although normal, was higher than in the control group (101 Ϯ 4 versus 86 Ϯ 2 mmHg, P Ͻ 0.01). After weight loss, BMI decreased by 32 Ϯ 4%, to 32.1 Ϯ 1.5 (P ϭ 0.001). GFR and RPF decreased to 110 Ϯ 7 ml/min (P ϭ 0.01) and 698 Ϯ 42 ml/min (P Ͻ 0.02), respectively. Albumin excretion rate decreased from 16 g/min (range, 4 to 152 g/min) to 5 g/min (range, 3 to 37 g/min) (P Ͻ 0.01). Fractional clearance of albumin decreased from 3.2 ϫ 10 Ϫ6 (range, 1.1 to 23 ϫ 10Ϫ6 (range, 0.5 to 6.8 ϫ 10 Ϫ6) (P Ͻ 0.02). This study shows that obesity-related glomerular hyperfiltration ameliorates after weight loss. The improvement in hyperfiltration may prevent the development of overt obesity-related glomerulopathy.Severe obesity is associated in with increased systemic arterial pressure (1), high renal plasma flow (2-4), increased GFR (2,5), and enhanced albumin excretion rate (6,7). We have previously studied glomerular hemodynamics in patients with severe obesity by measuring the fractional clearances of dextrans of broad size distribution (8). Analysis of the dextran sieving data, using a theoretical model of macromolecule transport through a heteroporous membrane, showed that the glomerular capillary bed was subjected to an elevated transcapillary hydraustatic pressure gradient resulting in hyperfiltration. In addition to these physiologic abnormalities, many reports have associated obesity with the occurrence of nephrotic syndrome and renal failure (9 -19). Obesity-related glomerulopathy was recently defined morphologically as glomerulomegaly with or without focal segmental glomerulosclerosis (20). Obesity may also accelerate the course of idiopathic glomerular disease, such as IgA glomerulopathy (21). The prevalence of obesity-related glomerulopathy, which may lead to end-stage renal disease, has increased tenfold over the last 15 yr as a consequence of "the spread of the obesity epidemic" (22). Although a cause-and-effect relationship between the obesityassociated glomerular hyperfunction and the development of nephrotic syndrome and renal failure has not been demonstrated, experimental and clinical data suggest that hyperfiltration and glomerulomegaly may lead to glomerular damage. Therefore, reducing glomerular hyperfiltration may provide a way to prevent or delay the deve...

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“…Upregulation of TGF-β has also been demonstrated in stroke-prone spontaneously hypertensive rats [13](possibly due to expression by mesangial cells associated with stretching forces [14, 15, 16]brought about by high intra-glomerular pressure). Although TGF-β has long been noted for its fibrogenic potential [12, 17, 18], recent studies suggest that TGF-β also influences lysosomal enzyme activity [19]. This may provide an interesting new mechanism for how TGF-β may be involved in the onset of albuminuria in both diabetes and in hypertension.…”

Section: Introductionmentioning

confidence: 99%

Renal Processing of Albumin in Diabetes and Hypertension in Rats

et al. 2003

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Background/Aims: Recent studies show that albuminuria may be the result of changes in post-glomerular cellular uptake and processing of albumin. This study aims to determine whether this processing is disrupted in diabetes and/or hypertension. Methods: Diabetes (d) was induced using streptozotocin in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) and studied after 8, 16 and 24 weeks of disease. Intact albumin excretion was determined by radioimmunoassay. Total albumin was determined by [¹⁴C]albumin. Lysosomal activity was determined by dextran sulfate desulfation. Renal TGF-β1 and transforming growth factor-β1 inducible gene-h3 mRNA (βig-h3) expression was determined by real time RT-PCR. Results: SHR-c rats exhibited an increase in intact albuminuria without significant change in total albumin excretion (intact plus albumin-derived peptides). For WKY-d rats, intact albuminuria developed initially, followed by an increase in total albumin excretion primarily in the form of albumin peptides (peptiduria). SHR-d rats exhibited both increases in peptiduria and intact albuminuria. There was no increase in glomerular permeability at 24 weeks for polydisperse [³H]Ficoll in all groups. Increased renal TGF-β1 and βig-h3 expression was correlated with a decrease in dextran sulfate desulfation and increased intact albuminuria independent of peptiduria. Conclusion: Increased albumin excretion in hypertension and/or diabetes is manifested in different forms independent of glomerular permeability.

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High-Glucose Media Enhance the Responsiveness of Tubular Cells to Growth Promoters: Effect on Lysosomal Cathepsins and Protein Degradation

Cited by 16 publications

References 28 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

The Effects of Weight Loss on Renal Function in Patients with Severe Obesity

Renal Processing of Albumin in Diabetes and Hypertension in Rats

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