**6. Angiogenic growth factors in ADPKD kidneys**

Angiogenesis is mediated by a shift in the balance towards expression of pro-angiogenic growth factors with concomitant decrease in anti-angiogenic factors. VEGF expression by renal cystic tubular epithelial cells and VEGFR-2 expression in endothelial cells in the small capillaries surrounding the cysts was demonstrated by Bello-Reuss et al. (Bello-Reuss et al., 2001). This contrasts with normal adult kidney where only weak expression of VEGF and VEGFR-2 are present in the collecting duct and surrounding capillaries (Simon et al., 1995). The demonstration of MMP-2 and integrin v3 on the endothelial surface of blood vessels in ADPKD kidneys by the same authors further affirms the presence of components necessary for angiogensis in ADPKD kidneys. Subsequent studies in a rat model of polycystic kidney disease demonstrated increased expression of VEGF in the kidneys and sera of the cystic animals compared to control animals (Tao et al., 2007). Similarly, increased expression of both VEGF receptors, VEGFR1 and VEGFR2 was demonstrated in renal tubular epithelial cells in the polycystic kidneys of these animals. We have also demonstrated expression of Ang-2 and the Tie-2 receptor by cyst lining epithelial cells of human polycystic kidneys as illustrated in Figure 1 (unpublished data).

Fig. 1. Expression of Ang-2 (A) and Tie-2 (B) by ADPKD cyst lining cells. Arrows indicate cyst lining cells with Ang-2 staining shown by lighter shading in A and Tie-2 staining by lighter speckled shading in B.

These observations suggest a mechanism whereby secretion of pro-angiogenic growth factors by the cyst lining epithelial cells may result in stimulated growth of the blood vessels surrounding the cysts thus facilitating cyst growth as illustrated in Figure 2.

Reuss et al. presented evidence of angiogenesis in human ADPKD kidneys based on angiographic studies (Bello-Reuss et al., 2001). These studies illustrated development of a well-defined vascular capsule around human renal cysts in ADPKD. Many morphological malformations were shown in the cyst wall vessels including presence of spiral, tortuous, and dilated vessels. This aberrant morphology is also typical in tumors further illustrating similarities between ADPKD cyst growth and growth of a benign tumor. A later study by the same group using corrosion cast studies of human ADPKD kidneys confirmed the occurrence of angiogenesis (Wei et al., 2006). This study also reported loss of the normal kidney vascular architecture in addition to evidence of microvascular regression. The pathological changes related to angiogenesis in ADPKD may also result in increased

Angiogenesis is mediated by a shift in the balance towards expression of pro-angiogenic growth factors with concomitant decrease in anti-angiogenic factors. VEGF expression by renal cystic tubular epithelial cells and VEGFR-2 expression in endothelial cells in the small capillaries surrounding the cysts was demonstrated by Bello-Reuss et al. (Bello-Reuss et al., 2001). This contrasts with normal adult kidney where only weak expression of VEGF and VEGFR-2 are present in the collecting duct and surrounding capillaries (Simon et al., 1995). The demonstration of MMP-2 and integrin v3 on the endothelial surface of blood vessels in ADPKD kidneys by the same authors further affirms the presence of components necessary for angiogensis in ADPKD kidneys. Subsequent studies in a rat model of polycystic kidney disease demonstrated increased expression of VEGF in the kidneys and sera of the cystic animals compared to control animals (Tao et al., 2007). Similarly, increased expression of both VEGF receptors, VEGFR1 and VEGFR2 was demonstrated in renal tubular epithelial cells in the polycystic kidneys of these animals. We have also demonstrated expression of Ang-2 and the Tie-2 receptor by cyst lining epithelial cells of

vascular permeability thus facilitating fluid secretion into cysts (Wei et al., 2006).

human polycystic kidneys as illustrated in Figure 1 (unpublished data).

lighter speckled shading in B.

**A** 

**Cyst** 

Fig. 1. Expression of Ang-2 (A) and Tie-2 (B) by ADPKD cyst lining cells. Arrows indicate cyst lining cells with Ang-2 staining shown by lighter shading in A and Tie-2 staining by

**B** 

**Cyst** 

These observations suggest a mechanism whereby secretion of pro-angiogenic growth factors by the cyst lining epithelial cells may result in stimulated growth of the blood vessels

surrounding the cysts thus facilitating cyst growth as illustrated in Figure 2.

**6. Angiogenic growth factors in ADPKD kidneys** 

Fig. 2. Release of angiogenic growth factors by cyst lining and other cells in response to hypoxic stimulus stimulates angiogenesis.

However, the nature of renal injury in ADPKD is complex, apoptosis and loss of endothelium occurs which correlates with the severity of glomerular sclerosis and interstitial fibrosis (Wei et al., 2006). Thus both indication of angiogenesis and destabilization of the existing vasculature are apparent in ADPKD kidneys. This is supported by demonstration that changes in renal blood flow parallel increase in total kidney volume and precede decline in renal function measured by change in glomerular filtration rate (GFR) in ADPKD (Torres et al., 2007).
