**7. Conclusion**

20 Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

In the kidneys of *mgb-/-* mice, fibrotic changes are observed in a distinctive pattern. Increased interstitial collagen deposition is first apparent in the renal parenchyma immediately subadjacent to the urothelium of the renal capsule, followed by the outer cortex near the renal capsule. In severe cases, fibrosis ultimately extends throughout the renal parenchyma. Altered patterns of -smooth muscle isoactin (-SMA), E-cadherin, TGF-1 and connective tissue growth factor expression are also observed in *mgb-/-* kidneys, supporting a role for these pathways in the development of fibrosis associated with congenital obstructive nephropathy (Ingraham, et al., 2010). Severely affected *mgb-/-* kidneys also display several dysplastic features including alteration in the developmental distribution of WT1 and PAX2. These observations are consistent with Edith Potter's classic work suggesting that the renal pathology associated with CAKUT includes varying degrees of renal hypodysplasia (Potter, 1972). In contrast to the well-characterized UUO model of upper urinary tract obstruction, inflammation does not appear to play a prominent or early

Fig. 7. Megabladder (*mgb*) mouse. **A.** Two *mgb-/-* mice, prior to (right) and immediately after (left) cutaneous vesicostomy. The mouse on the right demonstrates a massively distended abdomen secondary to the megabladder, whereas the mouse on the left demonstrates the flat belly attained with decompression of the bladder. **B.** Upon dissection and with the megabladder (MGB) reflected caudally, hydroureteronephrosis involving both kidneys (RK and LK) is apparent. **C.** Trichrome staining demonstrates a band of fibrosis (white arrows) underlying the urothelium in a mildly affected *mgb-/-* mouse. **D.** In a more severely affected kidney from a *mgb-/-* mouse, interstitial fibrosis (blue staining) extends throughout the renal medulla, and in a stripe along the outer cortex (yellow arrows) adjacent to the renal capsule.

role in the pathogenesis of renal injury in the megabladder model.

Morbidity and mortality remain very high for patients with congenital obstructive nephropathy, with few effective therapeutic options. Clearly, additional research is needed to illuminate the cellular and molecular changes that characterize congenital obstructive nephropathy, with particular emphasis on developing reliable biomarkers and new therapeutic approaches to reduce the impact of this devastating disease. Experimental animal models of obstructive nephropathy have provided valuable information regarding renal pathogenesis and function following surgical occlusion or genetic manipulation. The continued development of new animal models of congenital obstructive nephropathy, like the *mgb* mouse, will provide increasing opportunities to identify and manipulate the key molecular pathways associated with the development of chronic renal failure, while at the same time providing an experimental platform for biomarker development and the assessment of novel therapeutic strategies.
