**6. ECM on UPJ obstruction**

ureteropelvic junction (UPJ) obstruction and ureterovesical junction (UVJ) obstruction [9, 22–

The bladder ECM consists of proteins, proteoglycans and GAGs. ECM in bladder provides support and signaling to the cells of the bladder [25]. ECM components have an important role in the protection of urothelium and the storage of urine. The protective layer of GAGs (predominantly chondroitin and heparan sulfates) that cover urothelial cells forms a barrier

Bladder lamina propria forms a highly effective barrier between epithelial and mesenchymal layers. It consists of mainly connective tissue and it also contains myofibroblasts, nerve fibers,

Detrusor muscle is associated with laminin, osteopontin and collagen fibrils (I and III) During physiologic bladder filling and emptying, keratoepithelin is organized in complex folds and facilitates expansion and compaction of the bladder. Further, the ECM composition of the bladder wall, and in particular the type of collagen (type I favored in normally compliant bladders), as well as the collagen-to-elastin ratio, are critical to the maintenance of a low-

Studies on bladder cancer show that changes in ECM play a crucial role in the course of the disease. It has been shown that bladder cancer cells cultured in a normal ECM lose their invasiveness or ability to form papillary structures. Instead, they align in either multi- or single-

Altered distribution of laminin-5 γ2-chain is found to be associated with worse overall survival, higher risk of recurrence and progression; and it is regarded as independent prog‐ nostic factor in bladder cancer treated with TUR-B. Studies demonstrated that loss of collagen

Fibronectin is found at increased levels in lamina propria and in urine in urothelial carcinoma. Increased expression of it is also found to be associated with stage of the cancer but has no prognostic value. Increased value of fibronectin in urine suggested to be used for early detection of the tumor whereas decreased fibronectin level in the urine can be used to assess

Increased stromal expression of tenascin C is found to be associated with worse overall survival in bladder cancer; on the contrary tumor cell expression of tenascin C is associated with improved overall survival [29]. It is also found that in patients with decreased expression levels

In the function and diseases of prostate the noncellular stroma and ECM of the organ play an important role. Prostate basement membrane contains type IV and V collagen meshwork that is laminin rich and supports basal cells, stem cells, transit-amplifying cells and secretory

IV was associated with invasive behavior and worse overall survival [29].

of TSP-1, high rate of recurrence and worse overall survival is seen [29].

24].

**5.2. Bladder and lower urinary system**

228 Composition and Function of the Extracellular Matrix in the Human Body

against various toxic components [25].

lymphatics and blood vessels [26, 27].

pressure state in the bladder during normal filling [21].

layered formation resembling normal urothelium [28].

response to Bacillus Calmette Guérin (BCG) therapy [29].

epithelium.

Total or partial blockage at the level where renal pelvis and the ureter are joined is defined as UPJ obstruction. Obstruction can be congenital or acquired. In this case, the passage of urine from the kidney to the ureter was damaged partially or completely, depending on the grade of the obstruction. As a result, deterioration in renal function due to hydronephrosis may occur in untreated cases in the future.

In a normal kidney, the UPJ does not differ histologically from the renal pelvis. However, in an obstructed kidney, the longitudinal muscle fibers are significantly increased with more collagen deposits around the muscle fibers in addition to attenuation of muscle bundles [21].

The role of ECM in the pathogenesis of UPJ obstruction is still unclear. Major pathologic component of obstructive renal injury is tubulointerstitial fibrosis, which results in obstruc‐ tion-induced renal dysfunction. Tubulointerstitial fibrosis is regarded as the final common pathway for all kidney diseases that lead to chronic renal failure [30]. One of the earliest histologic changes in the obstructed kidney is an increase in inflammatory cell infiltration into the interstitial compartment of the kidney. This results in the secretion of growth factors and cytokines. As a response to increased cytokine and growth factor levels, matrix-producing fibroblasts accumulate in renal interstitium. In response to stimulation from cytokines and growth factors, fibroblasts will secrete collagen, elastin, proteoglycans and fibronectin into the interstitial space. MMPs strictly regulate ECM secretion process in healthy individuals. Tissue inhibitors of MMPs (TIMPs) are produced by both tubular cells and interstitial cells in the kidney, and they function to inhibit the activity of MMPs [21]. An increase in TIMPs expression has been shown as a result of urinary obstruction. Although it is thought that this mechanism could be the result of ECM accumulation the role of MMPs on renal fibrosis is still not clear. Some studies show that inhibition of MMPs results in increased renal fibrosis [31] whereas there is evidence that MMP-9-deficient mice have a dramatic reduction on interstitial fibrosis in response to urinary obstruction [32].

Kaya et al. show that there seems to be increased expression of ECM components in the patients with congenital UPJ obstruction. In their study, surgical specimens of 21 patients who underwent a pyeloplasty surgery were examined immunohistochemically. Their study showed that collagen III and tenascin C expression was significantly higher in patients with UPJ obstruction. Their study also reveals that in UPJ obstruction MMP-2 expression was significantly elevated compared with healthy controls, which represents increased matrix turnover. This study also showed decreased S100 protein expression emphasizing decreased neural structure which helps us to better understand pathophysiology of this condition [9].

Another study performed by Kim et al. [33] in 65 patients demonstrated that the more collagen compared to smooth muscle the worse renal function recovery after surgery. Although this study showed that increased collagen levels are associated with poor prognosis it lacks to investigate relations with collagen subgroups.

Supporting these findings, in 2009, Özel et al. performed a controlled study with 36 patients performing immunohistochemistry and found that fibronectin, type 4 collagen and laminin levels were significantly higher in patients with UPJ obstruction. They also expressed that apoptosis was higher in UPJ obstruction group [34].

Although it is a highly investigated area, role of ECM proteins in the development of UPJ obstruction and their impact on treatment success is still controversial. Current literature lacks a study that compares child and adult patient populations, which could give us a clearer picture for the progression of UPJ obstruction thought the life. Such information could help the physician to decide the timing of the surgery with more objective data.
