Transforming Growth Factor-β1 Is Up-Regulated by Podocytes in Response to Excess Intraglomerular Passage of Proteins

Abbate, Mauro; Zoja, Carla; Morigi, Marina; Rottoli, Daniela; Angioletti, Stefania; Tomasoni, Susanna; Zanchi, Cristina; Longaretti, Lorena; Donadelli, Roberta; Remuzzi, Giuseppe

doi:10.1016/s0002-9440(10)64495-1

Cited by 139 publications

(124 citation statements)

References 61 publications

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“…61,62 TGF-␤ is known to alter albumin permeability before up-regulation of ECM genes, 63 and TGF-␤ is increased by podoctyes exposed to excess intraglomerular albumin/proteins. 64 Treatment of mesangial cells with high levels of amino acids increases TSP1 expression and TSP1-dependent TGF-␤ activity, 65 and glycated albumin increases TSP1 expressed by cultured renal tubular cells, with increases in TSP1-dependent TGF-␤ activation. 38 These data suggest that TSP1 has a significant effect on proteinuria through regulation of TGF-␤ activity.…”

Section: Discussionmentioning

confidence: 99%

“…61 The present findings are unusual in that mesangial sclerosis was not affected by LSKL treatment but albuminuria was reduced. Given the known effects of TSP1 and LSKL peptide on blockade of glucose-stimulated TGF-␤ activity and matrix production by cultured mesangial cells and the reduced mesangial sclerosis in diabetic TSP1 knockout mice, 33,36,64 it is possible that mesangial accessibility of LSKL peptide administered i.p. was insufficient to attenuate glomerulosclerosis, although the effects of LSKL on nephrin expression and glomerular phospho-Smad levels suggest that the peptide is accessible.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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“…13,14 It is known that proteinuria is associated with the risk of cardiovascular disease. [15][16][17] Therefore, because of the antiproteinuric effect, benidipine would seem to be more advantageous than an L-type CCB, not only by slowing the progression of renal tissue injuries but also by reducing the incidence of cardiovascular events in patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

et al. 2010

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Benidipine inhibits both L-and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-tomoderate stage chronic kidney disease (CKD). Patients with BPX130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30-90 ml min À1 per 1.73 m 2 , and with albuminuria430 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n¼52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10 mg per day (n¼52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

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“…Our data are fully consistent with a role of protein overload of glomerular epithelial cells in the development of the sclerotic lesion in proteinuric disease. 42 This possibility is strengthened by findings that C3 deficiency attenuated podocyte damage and sclerosis in Adriamycin nephropathy in mice, and, conversely, CD59 deficiency exacerbated the disease. 43 Because podocytes normally express complement inhibitory molecules such as complement receptor 1 or its mouse analogue factor H, 44 it is reasonable to suggest that perturbed complement regulation may represent an important feature of this process.…”

Section: Both In C3mentioning

confidence: 99%

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Abbate

Zoja

Corna

et al. 2008

Journal of the American Society of Nephrology

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Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.

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Transforming Growth Factor-β1 Is Up-Regulated by Podocytes in Response to Excess Intraglomerular Passage of Proteins

Cited by 139 publications

References 61 publications

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

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