thymosin and Renal-Insufficiency--Chronic

Diseases affecting the glomerulus, the filtration unit of the kidney, are a major cause of chronic kidney disease. Glomerular disease is characterised by injury of glomerular cells and is often accompanied by an inflammatory response that drives disease progression. New strategies are needed to slow the progression to end-stage kidney disease, which requires dialysis or transplantation. Thymosin β4 (Tβ4), an endogenous peptide that sequesters G-actin, has shown potent anti-inflammatory function in experimental models of heart, kidney, liver, lung, and eye injury. In this review, we discuss the role of endogenous and exogenous Tβ4 in glomerular disease progression and the current understanding of the underlying mechanisms.

Topics: Disease Progression; Humans; Kidney Glomerulus; Renal Dialysis; Renal Insufficiency, Chronic; Thymosin

There is an urgent need for new treatments for chronic kidney disease (CKD). Thymosin-β4 is a peptide that reduces inflammation and fibrosis and has the potential to restore endothelial and epithelial cell injury, biological processes involved in the pathophysiology of CKD. Therefore, thymosin-β4 could be a novel therapeutic direction for CKD.. Here, we review the current evidence on the actions of thymosin-β4 in the kidney in health and disease. Using transgenic mice, two recent studies have demonstrated that endogenous thymosin-β4 is dispensable for healthy kidneys. In contrast, lack of endogenous thymosin-β4 exacerbates mouse models of glomerular disease and angiotensin-II-induced renal injury. Administration of exogenous thymosin-β4, or its metabolite, Ac-SDKP, has shown therapeutic benefits in a range of experimental models of kidney disease.. The studies conducted so far reveal a protective role for thymosin-β4 in the kidney and have shown promising results for the therapeutic potential of exogenous thymosin-β4 in CKD. Further studies should explore the mechanisms by which thymosin-β4 modulates kidney function in different types of CKD. Ac-SDKP treatment has beneficial effects in many experimental models of kidney disease, thus supporting its potential use as a new treatment strategy.

Topics: Animals; Disease Models, Animal; Fibrosis; Humans; Inflammation; Kidney; Mice; Mice, Transgenic; Renal Insufficiency, Chronic; Thymosin

Chronic kidney disease represents a dramatic worldwide resource-consuming problem. This problem is of increasing importance even in preterm infants, since nephrogenesis may go on only for a few weeks (4 to 6 weeks) after birth. Recent literature focusing on traditional regenerative medicine does not take into account the presence of a high number of active endogenous stem cells in the preterm kidney, which represents a unique opportunity for starting regenerative medicine in the perinatal period. Pluripotent cells of the blue strip have the capacity to generate new nephrons, improving kidney function in neonates and potentially protecting them from developing chronic kidney disease and end-stage renal disease in adulthood. There is a marked interindividual neonatal variability of nephron numbers. Moreover, the renal stem/progenitor cells appear as densely-packed small cells with scant cytoplasm, giving rise to a blue-appearing strip in hematoxylin-eosin-stained kidney sections ("the blue strip"). There are questions concerning renal regenerative medicine: among preliminary data, the simultaneous expression of Wilms tumor 1 and thymosin β4 in stem/progenitor cells of the neonatal kidney may bring new prospects for renal regeneration applied to renal stem cells that reside in the kidney itself. A potential approach could be to prolong the 6 weeks of postnatal renal growth of nephrons or to accelerate the growth of nephrons during the 6 weeks or both. Considering what we know today about perinatal programming, this could be an important step for the future to reduce the incidence and global health impact of chronic kidney disease.

Topics: Adult; Aging; Cell Differentiation; Female; Genes, Wilms Tumor; Humans; Infant; Infant, Newborn; Infant, Premature; Kidney; Nephrons; Pregnancy; Regenerative Medicine; Renal Insufficiency, Chronic; Stem Cells; Thymosin

Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin β4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-β1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin β4 and TGF-β1) influenced by DPP-4 inhibition.

Topics: Animals; Collagen Type I; Collagen Type I, alpha 1 Chain; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Down-Regulation; Glucagon-Like Peptide-1 Receptor; Heterogeneous Nuclear Ribonucleoprotein A1; Humans; Kidney; Linagliptin; Male; Mice; Mice, Knockout; Nephrectomy; Renal Insufficiency, Chronic; RNA-Seq; Signal Transduction; Thymosin; Transcription Factors; Transforming Growth Factor beta1; Up-Regulation

Therapies that modulate inflammation and fibrosis have the potential to reduce the morbidity and mortality associated with chronic kidney disease (CKD). A promising avenue may be manipulating thymosin-β4, a naturally occurring peptide, which is the major G-actin sequestering protein in mammalian cells and a regulator of inflammation and fibrosis. Thymosin-β4 is already being tested in clinical trials for heart disease and wound healing. This editorial outlines the evidence that thymosin-β4 may also have therapeutic benefit in CKD.

Topics: Adult; Animals; Fibrosis; Humans; Inflammation; Kidney; Mice; Rats; Renal Insufficiency, Chronic; Thymosin; Wound Healing