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

Abstract

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...

Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

“…Further, increased TGF-␤ in diabetes and hypertension is linked to disrupted albumin degradation through the inhibition of renal lysosomal activity (3,19,21,39). This may influence both the uptake and degradation of albumin, resulting in increased excretion of intact albumin or "albuminuria."…”

“…TGF-␤-related reductions in lysosomal activity may also alter the lysosomal processing of filtered albumin (3,19 -21) including its uptake and degradation, thus directly affecting the level of intact (immunodetectable) urinary albumin excretion. Using the opossum kidney cell model that expresses the albumin binding receptors megalin and cubilin, Gekle et al (22) directly demonstrated that TGF-␤1 reduces the expression of the albumin binding receptor megalin and affects the uptake of albumin in vitro (22), suggesting a direct role for TGF-␤ in the induction of albuminuria, as also suggested in studies by Russo and coworkers (3,21).…”

Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-β to prevent human essential hypertension

“…Elevated plasma TGF-b concentrations were noted in patients with albuminuria in hypertension and diabetic nephropathy, whereas angiotensin receptor blockers and ACE inhibitors decreased its excretion. This indicates that hyperexpression of TGF-b is an indicator of promotion of vascular and renal disease (Esmatjes et al, 2001;Wong et al, 2001;Agarwal et al, 2002;Houlihan et al, 2002;Russo et al, 2002). Angiotensin II cooperates with endothelin and TGF-b to activate collagen type I gene, resulting in the increased formation of extracellular matrix protein in the renal cortex and aorta (Fakhouri et al, 2001).…”

Gender Difference in Albuminuria and Ischemic Heart Disease in Type 2 Diabetes

“…1,2 Albuminuria in hypertensive patients is associated with altered lysosomal activity and transforming growth factor beta 1 (TGF-b1) expression. 3 Studies have substantially shown an increased risk of renal damage in the presence of cardiovascular risk factors in normal subjects as well as those with type 2 diabetes. 4,5 Ischemic heart disease is the major cause of morbidity and mortality in patients with type 2 diabetes, especially in those with elevated levels of urinary albumin excretion.…”