13 research outputs found
Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-ß antibody in \u3ci\u3edb/db\u3c/i\u3e diabetic mice
Emerging evidence suggests that transforming growth factor-(TGF-β) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-antibody (αT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of αT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with α or control IgG, 300 µg three times per week for 8 wk. Treatment with αT, but not with IgG, significantly decreased the plasma TGF-β1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding α 1(IV) collagen and fibronectin. On the other hand, treatment with α completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by α treatment. We conclude that chronic inhibition of the biologic actions of TGF-with neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type diabetes
Effects of high glucose and TGF-β1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes
Effects of high glucose and TGF-β1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes.BackgroundThe podocyte takes center stage in the pathogenesis of glomerular basement membrane (GBM) thickening and proteinuria in diabetic glomerulopathy. In part, GBM thickening may occur when the podocyte synthesizes increased amounts of collagen IV. Proteinuria may develop if the podocyte secretes excessive amounts of vascular endothelial growth factor (VEGF), which may increase the glomerular permeability to macromolecules. The augmented production of collagen IV and VEGF may be caused by metabolic mediators of diabetes such as hyperglycemia and transforming growth factor-β (TGF-β).MethodsThe effects of high glucose and exogenous TGF-β1 were examined on a mouse podocyte cell line that retains its differentiated phenotype. The gene expression and protein production of certain alpha chains of collagen IV, the major isoforms of VEGF, and components of the TGF-β system were assayed. An inhibitor of TGF-β signaling was used to determine whether some of the high glucose effects might be mediated by the TGF-β system.ResultsCompared with normal glucose (5.5 mmol/L), high glucose (HG, 25 mmol/L) for 14 days stimulated [3H]-proline incorporation, a measure of collagen production, by 1.8-fold, and exogenous TGF-β1 (2 ng/mL) for 24 hours stimulated proline incorporation by 2.4-fold. Northern analysis showed that exposure to HG for 14 days increased the mRNA level of α1(IV) collagen by 51% and α5(IV) by 90%, whereas treatment with TGF-β1 (2 ng/mL) for 24 hours decreased the mRNA level of α1(IV) by 36% and α5(IV) by 40%. Consistent with these effects on mRNA expression, Western blotting showed that HG increased α1(IV) protein by 44% and α5(IV) by 28%, while TGF-β1 decreased α1(IV) protein by 29% and α5(IV) by 7%. In contrast to their opposing actions on α1 and α5(IV), both HG and exogenous TGF-β1 increased α3(IV) collagen and VEGF, with TGF-β1 having the greater effect. An inhibitor of the TGF-β type I receptor (ALK5) was able to prevent the stimulation of α3(IV) and VEGF proteins by HG. Unlike in other renal cell types, HG did not increase TGF-β1 mRNA or protein in the podocyte, but HG did induce the expression of the ligand-binding TGF-β type II receptor (TβRII). Because HG had up-regulated TβRII after two weeks, the addition of physiological-dose TGF-β1 (0.010 ng/mL) for 24 hours stimulated the production of α3(IV) and VEGF proteins to a greater extent in high than in normal glucose. Up-regulation of TβRII in the podocyte was corroborated by immunohistochemistry of the kidney cortex in the db/db mouse, a model of type 2 diabetes.ConclusionsHigh glucose and exogenous TGF-β1 exert disparate effects on the expression of α1 and α5(IV) collagen. However, high glucose and TGF-β1 coordinately induce the production of α3(IV) collagen and VEGF in the podocyte. The HG-induced increases in α3(IV) collagen and VEGF proteins are mediated by the TGF-β system. By increasing the expression of TβRII, high glucose may augment the response of the podocyte to ambient levels of TGF-β1
Reduction in microalbuminuria as an integrated indicator for renal and cardiovascular risk reduction in patients
WSTĘP. Mikroalbuminuria u chorych na cukrzycę
typu 2 jest predyktorem nefropatii cukrzycowej oraz
chorób układu sercowo-naczyniowego. Celem niniejszego
badania obserwacyjnego była ocena efektu
klinicznego redukcji mikroalbuminurii u chorych na
cukrzycę typu 2.
MATERIAŁ I METODY. W ciągu pierwszych 2 lat badania
do projektu włączono 216 chorych na cukrzycę
typu 2 z mikroalbuminurią, których obserwowano
przez następne 8 lat. Za remisję lub 50-procentowe
zmniejszenie mikroalbuminurii przyjęto odpowiednio
powrót do wartości prawidłowych lub zmniejszenie
poziomu mikroalbuminurii o połowę w porównaniu
z poziomem wyjściowym. Analizowano
zależność między redukcją poziomu mikroalbuminurii
a czasem wystąpienia pierwszych objawów zaburzeń nerkowych lub sercowo-naczyniowych oraz
oznaczanym co roku wskaźnikiem estymowanej filtracji
kłębuszkowej (eGFR).
WYNIKI. W grupie 93 chorych z 50-procentowym
zmniejszeniem poziomów mikroalbuminurii odnotowano
12 incydentów nerkowych lub sercowo-naczyniowych
w porównaniu z 35 w grupie 123 chorych
bez takiej redukcji. Skumulowany wskaźnik częstości
wspomnianych powikłań cukrzycy był istotnie
mniejszy w grupie chorych z 50-procentową redukcją
poziomów mikroalbuminurii. Analiza przy użyciu sumarycznej
regresji logistycznej wykazała skorygowane
ryzyko powikłań 0,41 (95% CI: 0,15-0,96) u chorych
z 50-procentową redukcją mikroalbuminurii.
Oznaczany co roku wskaźnik spadku eGFR u tych
osób pogarszał się wolniej w porównaniu z grupą
bez 50-procentowej redukcji mikroalbuminurii. Podobne
dane uzyskano, analizując dane dotyczące
okresów remisji.
WNIOSKI. W przedstawionym badaniu dowiedziono,
że redukcja mikroalbuminurii u chorych na cukrzycę
typu 2 istotnie wpływa na zmniejszenie ryzyka powikłań
nerkowych i sercowo-naczyniowych cukrzycy.OBJECTIVE. Microalbuminuria in diabetic patients is
a predictor for diabetic nephropathy and cardiovascular
disease. The aim of this study is to investigate
the clinical impact of reducing microalbuminuria in
type 2 diabetic patients in an observational follow-up study.
RESEARCH DESIGN AND METHODS. We enrolled
216 type 2 diabetic patients with microalbuminuria
during an initial 2-year evaluation period and observed
them for the next 8 years. Remission and a 50%
reduction of microalbuminuria were defined as
a shift to normoalbuminuria and a reduction < 50%
from the initial level of microalbuminuria. The association
between reducing microalbuminuria and first
occurrence of a renal or cardiovascular event and
annual decline rate of estimated glomerular filtration
rate (eGFR) was evaluated.
RESULTS. Twelve events occurred in 93 patients who
attained a 50% reduction of microalbuminuria during
the follow-up versus 35 events in 123 patients
without a 50% reduction. The cumulative incidence
rate of events was significantly lower in patients
with a 50% reduction. A pooled logistic regression
analysis revealed that the adjusted risk for events in
subjects after a 50% reduction was 0.41 (95% CI:
0.15-0.96). In addition, the annual decline rate of
eGFR in patients with a 50% reduction was significantly
slower than in those without such a reduction.
The same results were also found in the analysis
regarding whether remission occurred.
CONCLUSIONS. The present study provides clinical
evidence implying that a reduction of microalbuminuria
in type 2 diabetic patients is an integrated indicator
for renal and cardiovascular risk reduction