Transgenic Expression of Nonclassically Secreted FGF Suppresses Kidney Repair

Abstract

FGF1 is a signal peptide-less nonclassically released growth factor that is involved in angiogenesis, tissue repair, inflammation, and carcinogenesis. The effects of nonclassical FGF export in vivo are not sufficiently studied. We produced transgenic mice expressing FGF1 in endothelial cells (EC), which allowed the detection of FGF1 export to the vasculature, and studied the efficiency of postischemic kidney repair in these animals. Although FGF1 transgenic mice had a normal phenotype with unperturbed kidney structure, they showed a severely inhibited kidney repair after unilateral ischemia/reperfusion. This was manifested by a strong decrease of postischemic kidney size and weight, whereas the undamaged contralateral kidney exhibited an enhanced compensatory size increase. In addition, the postischemic kidneys of transgenic mice were characterized by hyperplasia of interstitial cells, paucity of epithelial tubular structures, increase of the areas occupied by connective tissue, and neutrophil and macrophage infiltration. The continuous treatment of transgenic mice with the cell membrane stabilizer, taurine, inhibited nonclassical FGF1 export and significantly rescued postischemic kidney repair. It was also found that similar to EC, the transgenic expression of FGF1 in monocytes and macrophages suppresses kidney repair. We suggest that nonclassical export may be used as a target for the treatment of pathologies involving signal peptide-less FGFs.

Mouse model of ischemic acute kidney injury: technical notes and tricks

“…Nevertheless, in vivo whole animal models are indispensable, because of the limitation of the in vitro models to mimic the complexity of human body (45). Since the 1960s, various animal models of ischemic AKI have been developed and tested, and currently, two kinds of warm renal ischemia-reperfusion (IR) models are mainly used: 1) bilateral renal ischemic reperfusion (IR) (2-6, 8, 13, 14, 17, 19, 22, 23, 25-27, 30, 31, 35, 39, 41-43, 46, 51, 53-57, 59, 61, 63, 67, 68, 75-80) and 2) unilateral renal IR (1,9,15,18,20,21,24,29,33,34,37,38,40,44,50,58,60,62,64,66). Depending on whether the contralateral kidney is removed, the unilateral model can be further divided into two subtypes: unilateral IR with contralateral nephrectomy (15,18,20,29,38,40,44,50) or without contralateral nephrectomy (1,9,21,24,45,60).…”

FGF1 — a new weapon to control type 2 diabetes mellitus

“…However, whole-body knockout of FGF1 causes no change in tissue growth and the only known defects are adipose inflammation and a severe form of diabetes mellitus in response to dietary stress 32 . In addition, several transgenic mouse lines constitutively over-expressing FGF1 have no described tumours or organ growth, which suggests in vivo safety over long periods of exposure 131–133 . Gene expression array studies have found FGF1 levels increased in breast, prostate and ovarian cancers, but a contribution beyond correlation has not been established 129 .…”

Protein-Phospholipid Interactions in Nonclassical Protein Secretion: Problem and Methods of Study

“…Recombinant FGF1 has been used to accelerate the repair of wounds and post-ischemic tissues [42]. At the same time, natural or artificial FGF1 overexpression has been associated with tumorigenesis [33], hereditary hypertension [30], and fibrosis [43]. The nonclassical export of FGF1 was extensively studied using mouse fibroblasts [2].…”