Fibronectin Splice Variants – Prognostic Markers for the Stage of Renal Interstitial Fibrosis in the Rat

Abstract

Background/Aims: Renal interstitial fibrosis (RIF) is the main cause for progressive renal failure, but its pathogenic factors are not well known. In animal models of renal fibrogenesisdone thus far an increase of total fibronectin (FN) mRNA has been proved. Recent studies have pointed to a key role of the splice variant EIIIA⁺-FN and EIIIB⁺-FN for the development of organ fibrosis. However, a broader knowledge of the distribution of these different FN mRNA isoforms is still lacking. Our aim was to study the particular expression of the EIIIA⁺-FN and EIIIB⁺-FN during the process of fibrogenesis in two rat models and to evaluate the FN isoforms as diagnostic/prognostic marker for the stage of interstitial damage in rat kidneys. Methods: Kidneys of unilateral ureteral obstruction (UUO) and control rats were removed in intervals of 5, 14 or 21 days after surgery. For the investigation of kidney damage due to uranyl nitrate (UN), rats obtained a single i.p. dose of 5 mg/kg body weight UN and were killed 2, 10 and 20 weeks thereafter. The quantitative RT-PCR method was used to estimate the total FN, EIIIA⁺-FN and EIIIB⁺-FN transcription rate. Results: In the UUO model, a significant augmentation of both isoforms was obtained in the kidneys in the first 5-day interval, which was more pronounced at the 21-day interval. In the UN-treated kidneys there appeared only a continuous increase of EIIIA⁺-FN and the splice variant EIIIB⁺-FN failed to show a shift in these animals as compared to the controls. Conclusion: Both animal models generated fibrogenic damages of the tubulointerstitium, whereas only the UUO resulted in progressive fibrosis. Absence of EIIIB⁺-FN seems to enhance the progression of fibrogenesis.

Role of urotensin II in advanced glycation end product-induced extracellular matrix synthesis in rat proximal tubular epithelial cells

“…ColI, III, V and VII, and FN are normally distributed in the renal interstitium, while others such as laminin and ColIV are normally expressed in the basal membrane of the tubules. The expression of FN has been shown to be regulated by TGF-β, which is regarded as an early biomarker of fibrosis (29).…”

TGF-β and fibrosis in different organs — molecular pathway imprints

“…Excessive fibrosis, as it occurs under conditions of chronic myocarditis, can be classified as either replacement fibrosis, when functional tissue is replaced by connective tissue, or as reactive fibrosis, which is part of an adaptive process [139]. In addition to collagen, tenascin C, and fibronectin, splice variants of these molecules are often part of the fibrotic tissue [140,141]. Various cytokines and growth factors are believed to contribute to the induction of fibrosis, including TGF- [142], IL-1, [143], TNF- [144,145], and PDGFs [146,147].…”

Imatinib atenua a fibrose miocárdica em associação com a inibição da atividade do PDGFRα

“…In this study, the fibrosis of myocardium and tissues surrounding blood vessels in the DOCA + IMA group were markedly alleviated, and the protein expressions of PI and PIII significantly decreased when compared with the DOCA group. Fibronectin and tenascin-C are also major components of fibrotic tissues 39,40 . Tenascin-C has been found to be involved in the adhesion between myocardial cells and fibrotic tissues, and to regulate the fibroblast recruitment after myocardial injury.…”