Smad proteins and transforming growth factor-beta signaling (original) (raw)
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Life Sciences, 1998
Transforming growth factor-p (TGF-P) is a profibrotic cytokine which has been implicated in the renal fibrosis which follows unilateral ureteral obstruction (UUO) in the rat. TGF-P receptor type I (TGF-RI) and TGF-P receptor type II (TGF-RII) are part of the complex which mediates the response to TGF-P. We sought to determine if TGF-RI and TGF-RII are found in the kidney, and if their expression is changed as a result of UUO. Polymerase chain reaction (PCR) was used to determine expression of mRNA for TGF-RI and TGF-RII in the kidney. Immunoperoxidase was used to localize and quantify the expression of these receptors at 3,7,14,21 and 28 days after UUO, and in sham-operated animals. Expression of mRNA for TGF-RI and TGF-RII was demonstrated in sham operated, obstructed and contralateral unobstructed kidneys using PCR. Using immunoperoxidase, a uniform distribution of TGF-RI and TGF-RII was found in cortical tubules of sham operated kidneys, whereas medullary tubules showed a patchy TGF-RI distribution and no TGF-RII staining.
Redirection of renal mesenchyme to stromal and chondrocytic fates in the presence of TGF-β2
Differentiation, 2010
Many members of the transforming growth factor-b (TGF-b) superfamily have been shown to be important regulators of metanephric development. In this study, we characterized the effect of TGF-b2 on metanephric development. Rat and mouse metanephroi cultured in the presence of exogenous TGF-b2 for up to 15 days were small, and contained rudimentary ureteric branches and few glomeruli. These metanephroi were mostly comprised of mesenchymal cells, with two cell populations (designated Type 1 and Type 2 cells) evident. Type 1 cells were only observed when TGF-b2 was added from the commencement of culture, they resembled chondroblasts and were Alcian Blue and Col IIB positive. Type 2 cells were observed whenever TGF-b2 was added to the media, formed a band at the periphery of the explants consisting of 5-10 layers of spindle-shaped cells, and were alpha-smooth muscle actin positive. Molecular and RNA in situ hybridization analysis of metanephroi cultured in the presence of TGF-b2 for 6 days demonstrated that Type 1 and 2 cells were negative for Pax2, WT1, GDNF and FoxD1. Gene expression profiling demonstrated an upregulation of chondrocyte, myogenic and stromal genes, some of which were identified as markers of Type 1 and Type 2 cells. In addition, TGF-b2 was capable of maintaining the survival of mouse isolated metanephric mesenchyme (iMM) in the absence of serum or inductive signals from the ureteric epithelium. TGF-b2 also induced the differentiation of iMM into Type 1 and 2 cells. The presence of chondrocytes and muscle in these cultures is reminiscent of the cell types found in some Wilms' tumors. These studies demonstrate that TGF-b2 is capable of differentiating metanephric mesenchyme away from a renal cell fate.
In vitro studies on the roles of transforming growth factor-beta1 in rat metanephric development
Kidney International, 2001
In vitro studies on the roles of transforming growth factor-1 nephric development involves invasion of the ureteric in rat metanephric development. duct epithelium into a specialized mass of undifferenti-Background. The development of the permanent kidney ated mesenchyme, the metanephric mesenchyme. The (metanephros) involves the interplay between both positive and mesenchyme of the nephrogenic zone induces the urenegative regulatory molecules. Transforming growth factor-1 teric duct to branch and elongate. At the tips of the (TGF-1) has previously been shown to negatively regulate ureteric branches, inductive events signal nephron forureteric duct growth. However, its potential role in nephron development and glomerulogenesis has been largely ignored. mation from the mesenchyme cells of the nephrogenic Methods. In situ hybridization and reverse transcriptionzone. Nephron development proceeds with a mesenpolymerase chain reaction were employed to examine the temchyme to epithelial transition to form a vesicle. This is poral and spatial localization of TGF-1 mRNA and a TGF- followed by the formation of comma-shaped and S-shaped type I receptor (activin-like receptor kinase-5; ALK-5) mRNA in bodies, tubular differentiation, and glomerulogenesis. developing rat metanephroi. The addition of exogenous TGF-1 The results from several studies suggest a role for transto rat metanephric organ culture at different time points was used to examine the role of TGF-1 in ureteric duct growth forming growth factor- (TGF-) and its receptors in and nephron development. metanephric development [6-10]. In particular, TGF-1 Results. TGF-1 mRNA did not colocalize with ALK-5 has been shown to inhibit ureteric duct growth in vitro mRNA. Instead, TGF-1 mRNA colocalized with the TGF- [6, 7, 11]. The role of TGF-1 in glomerular development type II receptor mRNA. The addition of recombinant human and nephron formation, however, has not been thor-TGF-1 to rat metanephric organ culture at the beginning of oughly explored, although Lui, Dardik, and Ballermann the culture period inhibited total metanephric growth and the recently showed that TGF-1-neutralizing antibody regrowth of the ureteric tree, resulting in a decrease in nephron number. Similarly, the addition of TGF-1 to metanephroi duces the invasion of comma-and S-shaped bodies by after 48 hours of culture inhibited ureteric duct growth, deendothelial cells in vivo and inhibits formation of capilcreasing nephron number. The addition of TGF-1 at days 0 laries in these structures [12]. or 2 of culture promoted hypertrophy of the renal capsule. Transforming growth factor-1 interacts with three Conclusions. These findings confirm that TGF-1 inhibits receptor types called type I, type II, and type III TGF- ureteric duct growth and thereby nephron endowment in develreceptors. For signal transduction to occur, TGF-1 oping rat metanephroi in vitro. However, TGF-1 does not binds two TGF- type II receptors at the cell surface. appear to play a significant role in nephron development per se once the epithelial vesicle has formed.
Sustained hyperosmolarity increses TGF-ß1 and Egr-1 expression in the rat renal medulla
BMC Nephrology
Background: Although TGF-ß and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo-or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ß and Egr-1 expression. Methods: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. Results: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ß and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ß and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ß and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. Conclusion: We conclude that both TGF-ß and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components.
Transforming growth factor- and the progression of renal disease
Nephrology Dialysis Transplantation, 2014
Transforming growth factor-β (TGF-β) is a profibrotic cytokine found in chronic renal diseases, which initiates and modulates a variety of pathophysiological processes. It is synthesized by many renal cell types and exerts its biological functions through a variety of signalling pathways, including the Smad and MAPK pathways. In renal diseases, TGF-β is upregulated and induces renal cells to produce extracellular matrix proteins leading to glomerulosclerosis as well as tubulointerstitial fibrosis. Different types of renal cells undergo different pathophysiological changes induced by TGF-β, leading to apoptosis, hypertrophy and abnormalities of podocyte foot processes, which ultimately result in renal dysfunction. In this review, we describe the effects of TGF-β on different renal cell types and the means by which TGF-β participates in the pathomechanisms of glomerular and tubulointerstitial diseases.