**3. The Pathophysiology of Kidney Injury Caused by UUTO (Figure 1)**

Urinary tract obstruction affects renal function in many ways. The increase in intratubular hydrostatic pressure [9] triggers renopathogenic effects via three proposed mechanisms: tubular ischemia caused by hypoperfusion, pressure-induced mechanical stretching or compression of tubular cells, and altered urinary shear stress. The latter two mechanisms are likely the primary causes of obstructive renal injury [10], being associated with the dysregulation of many cytokines, growth factors, enzymes, and cytoskeletal proteins. Changes in early renal hemodynamics are followed by structural and functional changes in the entire nephron. The earliest stage of UUTO is associated with an increase in renal blood flow 1–2 h in duration [10]. The intrarenal renin–angiotensin–aldosterone system is then activated, which causes pre- and post-glomerular vasoconstriction and resultant drops in renal blood flow, medullary oxygen tension, and the glomerular filtration rate [11,12]. The increased intra-renal angiotensin II activates nuclear factor kappa B, triggering cytokine release and reactive oxygen species (ROS) production [2,10,13,14]. Adhesion molecules such as selectins attract

infiltrating macrophages, monocyte chemotactic protein-1 (MCP-1) is upregulated, and tumor necrosis factor-α (TNF-α) is released. Monocytes and macrophages are attracted to the tubular interstitium of the UUTO kidney [2,14,15]. Activated macrophages infiltrate the interstitium, sustaining the inflammatory response by releasing cytokines such as transforming growth factor-β1 (TGF-β1) and TNF-α and ROS [16]. ROS mediate the profibrotic action of TGF-β1, and renal fibrosis proceeds via the epithelial–mesenchymal transition (EMT) of renal tubular epithelial cells. The outcome is interstitial fibrosis caused by increased deposition of the extracellular matrix, cellular infiltration, tubular apoptosis, and the EMT [17]. The mechanical stretching of tubular cells, ischemia, and oxidative stress that follow ureteral obstruction cause tubular cell death [18,19]. Mild injury triggers apoptosis, while tubulointerstitial atrophy after obstruction causes cell deletion. The apoptotic bodies are phagocytosed by neighboring tubular cells or directly shed into the tubular lumen, reestablishing homeostasis. When the injury is severe, necrosis is likely to be the predominant cause of cell loss [19,20]. Increased apoptosis and/or necrosis activates cell infiltration, interstitial cell proliferation, and interstitial fibrosis (Figure 1).

Hydrostatic pressure stretches tubular cells and creates urinary shear stress, inducing intrarenal angiotensin II activation followed by the release of cytokines and adhesion molecules, in turn triggering macrophage infiltration, the production of reactive oxygen species (ROS), and decreased renal blood flow (RBF). The drop in RBF triggers renal ischemia, and the increase of hydrostatic pressure and ROS causes tubular cell death. Monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) released from activated macrophages, ROS, and/or tubular cell death induce the epithelial–mesenchymal transition (EMT) and fibroblast proliferation. Eventually the renal parenchyma is transformed into fibrotic tissue.

**Figure 1.** Mechanisms of UUTO causing kidney injury and fibrosis.
