Unilateral Ureteral Obstruction as a Model to Investigate Fibrosis-Attenuating Treatments

Abstract

Renal fibrosis is the common pathway for most forms of progressive renal disease. The Unilateral Ureteral Obstruction (UUO) model is used to cause renal fibrosis, where the primary feature of UUO is tubular injury as a result of obstructed urine flow. Furthermore, experimental UUO in rodents is believed to mimic human chronic obstructive nephropathy in an accelerated manner. Renal fibrosis is the common pathway for most forms of progressive renal disease. Removing the obstruction may not be sufficient to reverse fibrosis, so an accompanying treatment may be of benefit. In this review, we have done a revision on treatments shown to ameliorate fibrosis in the context of the UUO experimental model. The treatments inhibit the production of fibrotic and inflammatory proteins such as Transforming Growth Factor β1 (TGF-β₁), Tumor Necrosis Factor α (TNF-α), collagen and fibronectin, Heat Shock Protein 47 (HSP47), suppress the proliferation of fibroblasts, prevent epithelial-to-mesenchymal transition, reduce oxidative stress, inhibit the action of the Nuclear Factor κB (NF-κB), reduce the phosphorylation of mothers against decapentaplegic homolog (SMAD) family members 2 and 3 (Smad2/3) or Mitogen-Activated Protein Kinases (MAPKs), inhibit the activation of the renin-angiotensin system. Summaries of the UUO experimental methods and alterations observed in the UUO experiments are included.

Keywords: UUO; fibrosis; fibrosis-attenuating treatment; unilateral ureteral obstruction.

Figure 1

Summarized events that occur in the Unilateral Ureteral Obstruction-Obstructed Kidney (UUO-OK). The Unilateral Ureteral Obstruction (UUO) procedure typically consists of ligating one ureter with silk thread. Several variations on the technique have been reported and are listed in Table 1.

Figure 2

Smad-dependent onset of fibrosis. TGF-β₁ binds to TGF-β Receptors type I and II (TGF-βRI and TGFβ-RII), involving Smad2/3, which must become phosphorylated in order to form a complex with Smad4. Smad7 has the capacity to repress the complex. The complex translocates to the nucleus, where it is required for the transcription of their target fibrogenesis genes.

Figure 3

Chemical structures of vitamin and antioxidant compounds tested for fibrosis-ameliorating activity in the context of the UUO model. The structures were obtained from the PubChem database [60]: the “PubChem CID” for each compound has been listed in the text next to the compound’s name.

Figure 4

Chemical structures of pharmaceutical compounds tested for fibrosis-ameliorating activity in the context of the UUO model. The structures were obtained from the PubChem database [60]: the “PubChem CID” for each compound has been listed in the text next to the compound’s name.

Figure 5

Chemical structures of plant-derived compounds tested for fibrosis-ameliorating activity in the context of the UUO model. The structures were obtained from the PubChem database [60]: the “PubChem CID” for each compound has been listed in the text next to the compound’s name.

Figure 6

Chemical structures of purified or synthesized compounds and a selected recombinant protein tested for fibrosis-ameliorating activity in the context of the UUO model. The structures were obtained from the PubChem database [60]: the “PubChem CID” for each compound has been listed in the text next to the compound’s name.

Figure 7

Encompassing summary of the histological lesions, protein levels or protein activities in untreated UUO and treated-UUO. The “UUO” section is the comparison between the untreated-UUO groups and the Sham-groups, whereas the “Treated-UUO” section is a comparison between the untreated-UUO groups and the treated UUO-groups. Up-arrows indicate increase, down-arrows indicate decrease and gray-underline indicates unchanged levels.