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.
Highlights
Tranforming growth factor-ß (TGF-ß) and the transcription factor early growth response factor-1 (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
Increased osmolarity induces the expression of profibrotic genes in inner medullary collecting duct (IMCD) cells As TGF-ß is one of the key growth factors that participate in the pathomechanism of fibrosis, we investigated whether its increased expression due to hyperosmolarity could contribute to fibrotic gene expression in vitro
To the best of our knowledge, this is the first study to show that sustained hyperosmolar conditions maintained by water restriction induced the expression of Egr-1, TGF-ß and activator protein-1 (AP-1) component cFos in the renal medulla, which might upregulate the gene expression of collagens
Summary
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. Chronic kidney disease counts for a significant number of deaths worldwide, and its prevalence is estimated to be 8–16% [1]. Tranforming growth factor-ß (TGF-ß) has a major impact on fibrotic diseases, including myocardial, pulmonary and kidney fibrosis [3,4,5,6]. AP-1 can induce extracellular matrix accumulation through the activation of the tissue inhibitor of metalloprotease-1 (TIMP-1) expression [17]. The transcription factor AP-1 is a heterodimeric molecule, composed of Jun and Fos nuclear oncoprotein families, being c-Jun and c-Fos the two major components of AP-1 [21]
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