TGF-β1–Induced Glomerular Disorder Is Associated with Impaired Concentrating Ability Mimicking Primary Glomerular Disease with Renal Failure in Man

Abstract

SUMMARY:Transforming growth factor-␤1 (TGF-␤1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-␤1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-␤1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1 c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-␤1 reduces the GFR and the glomerular filtration surface, (b) TGF-␤1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-␤1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of

Infiltration of Canonical Vγ4/Vδ1 γδ T Cells in an Adriamycin-Induced Progressive Renal Failure Model

“…They did not express IL-4, IL-10, or IFN-␥. TGF-␤ contributes to the development of the renal fibrosis and sclerosis seen in this model (36) and other models of progressive glomerulonephritis (37)(38)(39)(40)(41)(42). It is possible that the production of TGF-␤ may be involved in the progressive renal failure.…”

Protease Nexin-1, tPA, and PAI-1 are Upregulated in Cryoglobulinemic Membranoproliferative Glomerulonephritis

“…PAI-1 can be induced by TGF-␤1 in rodent kidneys and in cultured mesangial cells. 22,23 TGF-␤1 transgenic mice developed expanded ECM, which was accompanied by increased levels of PAI-1 in vivo. 22 We previously reported upregulation of TGF-␤1 mRNA in glomeruli by ISH that parallels the accumulation of ECM proteins in TSLP mice 24 and now show that this correlates with upregulated PAI-1 expression.…”

“…22,23 TGF-␤1 transgenic mice developed expanded ECM, which was accompanied by increased levels of PAI-1 in vivo. 22 We previously reported upregulation of TGF-␤1 mRNA in glomeruli by ISH that parallels the accumulation of ECM proteins in TSLP mice 24 and now show that this correlates with upregulated PAI-1 expression. We suggest that PAI-1 plays an important role in the control of glomerular matrix accumulation in this murine model of MPGN as in other renal injuries and that the mech- anisms of the PAI-1-related glomerular ECM production might be mediated through cytokines such as TGF-␤1 released from intraglomerular macrophages and/or mesangial cells.…”

Expression of mTert in primary murine cells links the growth-promoting effects of telomerase to transforming growth factor-β signaling

“…In particular, upon treatment with TGF-b for 24 and 48 h, mTert overexpressing MEF cultures contained 2.470.6-fold (Po0.05) and 1.570.1-fold (Po0.01) more cells, respectively, than MEF cultures transduced with an empty vector (Figure 3b). In the context of the organism, TGF-b has been shown to have an important role in renal diseases (Kopp et al, 1996;Krag et al, 2000). Interestingly, we have previously described that mice that overexpress mTert are partially protected against degenerative kidney lesions such as glomerulonephritis (Gonzalez-Suarez et al, 2005).…”