Sustained hyperosmolarity increses TGF-ß1 and Egr-1 expression in the rat renal medulla

Abstract

BackgroundAlthough 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.MethodsMale 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.ResultsUrine 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.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-017-0626-2) contains supplementary material, which is available to authorized users.

High Salt Promotes Inflammatory and Fibrotic Response in Peritoneal Cells

“…Finally, our investigations revealed the role of high salt and osmotic conditions in the fibronectin and collagen production of HPFs ( Figure 6 A,B and Figure 7 J). In accordance with this Mózes et al demonstrated that a high osmotic environment induced by combination of NaCl and urea increased the Col3a1 and Col4a1 mRNA expression in cultured inner medullary collecting duct cells, suggesting that elevated sodium content alone can activate ECM production of tissue fibroblasts [ 64 ].…”

The PPARγ agonist pioglitazone prevents TGF-β induced renal fibrosis by repressing EGR-1 and STAT3

“…Other transcription factors, such as the immediate early gene EGR-1, might be induced by a variety of fibrogenic stimuli, directly stimulating collagen production, matrix accumulation and myofibroblast differentiation [6, 7]. We found boosted EGR-1 expression in untreated TGF-β 1 transgenic kidneys that was attenuated by pioglitazone treatment.…”

“…Among the several profibrotic transcription factors, early growth response factor-1 (EGR-1) contributes to fibrosis by directly stimulating collagen synthesis [6] and myofibroblast differentiation [7]. The Janus kinase family (JAK) and the signal transducers and activators of transcription (STATs) signaling pathways also play important role in several models of renal diseases [8–10].…”

Genetic or siRNA inhibition of MBD2 attenuates the UUO- and I/R-induced renal fibrosis via downregulation of EGR1

“…Early growth response protein 1 (EGR1), a member of the immediate–early response gene family, has been shown to mediate renal fibrosis induced by multiple growth factors. 21 , 22 , 23 , 24 , 25 , 26 Interestingly, another study reported that MeCP2 regulated EGR1 expression through binding to its CpG islands. 27 Thus, the role and mechanism of regulation for MBD2 in the expression of EGR1 remain unclear.…”