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Loss of endogenous thymosin ?4 accelerates glomerular disease.

ABSTRACT: Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin ?4 regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin ?4 improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin ?4 in the kidney is unknown. We demonstrate that thymosin ?4 is expressed prominently in podocytes of developing and adult mouse glomeruli. Global loss of thymosin ?4 did not affect healthy glomeruli, but accelerated the severity of immune-mediated nephrotoxic nephritis with worse renal function, periglomerular inflammation, and fibrosis. Lack of thymosin ?4 in nephrotoxic nephritis led to the redistribution of podocytes from the glomerular tuft toward the Bowman capsule suggesting a role for thymosin ?4 in the migration of these cells. Thymosin ?4 knockdown in cultured podocytes also increased migration in a wound-healing assay, accompanied by F-actin rearrangement and increased RhoA activity. We propose that endogenous thymosin ?4 is a modifier of glomerular injury, likely having a protective role acting as a brake to slow disease progression.

SUBMITTER: Vasilopoulou E

PROVIDER: S-EPMC5073078 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Loss of endogenous thymosin β4 accelerates glomerular disease.

Vasilopoulou Elisavet E Kolatsi-Joannou Maria M Lindenmeyer Maja T MT White Kathryn E KE Robson Michael G MG Cohen Clemens D CD Sebire Neil J NJ Riley Paul R PR Winyard Paul J PJ Long David A DA

Kidney international 20160826 5

Glomerular disease is characterized by morphologic changes in podocyte cells accompanied by inflammation and fibrosis. Thymosin β4 regulates cell morphology, inflammation, and fibrosis in several organs and administration of exogenous thymosin β4 improves animal models of unilateral ureteral obstruction and diabetic nephropathy. However, the role of endogenous thymosin β4 in the kidney is unknown. We demonstrate that thymosin β4 is expressed prominentl ...[more]

PMID: 27575556

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Project description:ObjectiveThymosin beta 4 (Tβ4) is a peptide with 43 amino acids that is critical for repair and remodeling tissues on the skin, eye, heart, and neural system following injury. To fully realize its utility as a treatment for disease caused by injury, the authors constructed a cost-effective novel Tβ4 dimer and demonstrated that it was better able to accelerate tissue repair than native Tβ4.MethodsA prokaryotic vector harboring two complete Tβ4 genes with a short linker was constructed and expressed in Escherichia coli. A pilot-scale fermentation (10 L) was performed to produce engineered bacteria and the Tβ4 dimer was purified by one-step hydrophobic interaction chromatography. The activities of the Tβ4 dimer to promote endothelial cell proliferation, migration, and sprouting were assessed by tetramethylbenzidine (methylthiazol tetrazolium), trans-well, scratch, and tube formation assays. The ability to accelerate dermal healing was assessed on rats.ResultsAfter fermentation, the Tβ4 dimer accounted for about 30% of all the bacteria proteins. The purity of the Tβ4 dimer reached 98% after hydrophobic interaction chromatography purification. An average of 562.4 mg/L Tβ4 dimer was acquired using a 10 L fermenter. In each assay, the dimeric Tβ4 exhibited enhanced activities compared with native Tβ4. Notably, the ability of the dimeric Tβ4 to promote cell migration was almost two times higher than that of Tβ4. The rate of dermal healing in the dimeric Tβ4-treated rats was approximately 1 day faster than with native Tβ4-treated rats.ConclusionThe dimeric Tβ4 exhibited enhanced activity on wound healing than native Tβ4, and the purification process was simple and cost-effective. This data could be of significant benefit for the high pain and morbidity associated with chronic wounds disease. A better strategy to develop Tβ4 as a treatment for other diseases caused by injuries such as heart attack, neurotrophic keratitis, and multiple sclerosis was also described.

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Loss of endogenous thymosin ?4 accelerates glomerular disease.

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Loss of endogenous thymosin β<sub>4</sub> accelerates glomerular disease.

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Loss of endogenous thymosin ?4 accelerates glomerular disease.

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Loss of endogenous thymosin β&lt;sub&gt;4&lt;/sub&gt; accelerates glomerular disease.

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OmicsDI is part of the ELIXIR infrastructure

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Loss of endogenous thymosin β<sub>4</sub> accelerates glomerular disease.