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.

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development - such as the activation of transforming growth factor-β and the deposition of extracellular matrix - have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.

INTRODUCTION:The current therapeutic armamentarium to prevent chronic kidney disease (CKD) progression is limited to the control of blood pressure and in diabetic patients, the strict control of glucose levels. Current research is primarily focused on the reduction of inflammation and fibrosis at different levels. AREAS COVERED:This article examines the latest progress in this field and places an emphasis on inflammation, oxidative stress, and fibrosis. New therapeutic targets are described and evidence from experimental and clinical studies is summarized. We performed a search in Medline for articles published over the last 10 years. EXPERT OPINION:The search for therapeutic targets of renal inflammation is hindered by an incomplete understanding of the pathophysiology. The determination of the specific inducers of inflammation in the kidney is an area of heightened potential. Prevention of the progression of renal fibrosis by blocking TGF-β signaling has been unsuccessful, but the investigation of signaling pathways involved in late stages of fibrosis progression could yield improved results. Preventive strategies such as the modification of microbiota-inducers of uremic toxins involved in CKD progression is a promising field because of the interaction between the gut microbiota and the renal system.

Chronic kidney disease (CKD) is a long-term condition in which the kidneys do not work correctly. It has a high prevalence and represents a serious hazard to human health and estimated to affects hundreds of millions of people. Diabetes and hypertension are the two principal causes of CKD. The progression of CKD is characterized by the loss of renal cells and their replacement by extracellular matrix (ECM), independently of the associated disease. Thus, one of the consequences of CKD is glomerulosclerosis and tubulointerstitial fibrosis caused by an imbalance between excessive synthesis and reduced breakdown of the ECM. There are many molecules and cells that are associated with progression of renal fibrosis e.g. angiotensin II (Ang II). Therefore, in order to understand the biopathology of renal fibrosis and for the evaluation of new treatments, the use of animal models is crucial such as: surgical, chemical and physical models, spontaneous models, genetic models and in vitro models. However, there are currently no effective treatments for preventing the progression of renal fibrosis. Therefore it is essential to improve our knowledge of the cellular and molecular mechanisms of the progress of renal fibrosis in order to achieve a reversion/elimination of renal fibrosis.

Renal interstitial fibrosis is the pathological basis of end-stage renal disease, in which the heterogeneity of macrophages in renal microenvironment plays an important role. However, the molecular mechanisms of macrophage plasticity during renal fibrosis progression remain unclear. In this study, we found for the first time that increased expression of Twist1 in macrophages was significantly associated with the severity of renal fibrosis in IgA nephropathy patients and mice with unilateral ureteral obstruction (UUO). Ablation of Twist1 in macrophages markedly alleviated renal tubular injury and renal fibrosis in UUO mice, accompanied by a lower extent of macrophage infiltration and M2 polarization in the kidney. The knockdown of Twist1 inhibited the chemotaxis and migration of macrophages, at least partially, through the CCL2/CCR2 axis. Twist1 downregulation inhibited M2 macrophage polarization and reduced the secretion of the profibrotic factors Arg-1, MR (CD206), IL-10, and TGF-β. Galectin-3 was decreased in the macrophages of the conditional Twist1-deficient mice, and Twist1 was shown to directly activate galectin-3 transcription. Up-regulation of galectin-3 recovered Twist1-mediated M2 macrophage polarization. In conclusion, Twist1/galectin-3 signaling regulates macrophage plasticity (M2 phenotype) and promotes renal fibrosis. This study could suggest new strategies for delaying kidney fibrosis in patients with chronic kidney disease.