**5. Evidence for angiogenesis in ADPKD kidneys**

Abnormalities of the renal vasculature in polycystic kidneys have long been recognized based on early angiographic studies of the kidney (Cornell, 1970, Ettinger et al., 1969) Bello-

Angiogenesis and the Pathogenesis of Autosomal Dominant Polycystic Kidney Disease 99

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

measured by change in glomerular filtration rate (GFR) in ADPKD (Torres et al., 2007).

**8. Serum levels of angiogenic growth factors are increased in ADPKD** 

sFlt1 may play a role in implenting disease progression in ADPKD.

We have previously reported that serum levels of VEGF and Ang-2 are elevated in children and young adults with ADPKD compared to age, sex, and renal function matched young subjects with diabetes as shown in Table 2 (Reed et al., 2011). In these children and young adults renal function was normal, mean eGFR 128 ml/min/1.73m2. The level of VEGF detected in renal cyst fluid was comparable to the mean serum level. The plasma levels of the soluble VEGF receptor (sFlt1), an antagonist of VEGF, rise progressively with declining renal function in patients with CKD (Di Marco et al., 2009). The same study demonstrated an association between plasma sFlt1 level and endothelial dysfunction. In our own study we found that serum levels of sFlt1 ranged between <13-320 pg/ml in ADPKD patients, however normal healthy serum values were not available for comparison (unpublished data) (Table 2). It is important to note that both the circulating level of VEGF and level of the VEGF antagonist

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

Expression of angiogenic growth factors have also been demonstrated in cystic liver from human ADPKD patients and also in animal models of PKD.Upregulated expression of Ang-1, Ang-2 and their Tie-2 receptor has been demonstrated in the cholangiocytes that line hepatic cysts in ADPKD, supporting a role for angiogenic growth factors in liver cystogenesis (Fabris et al., 2006). Moreover, cyst fluid from hepatic cysts has been shown to contain VEGF (Amura et al., 2008; Nichols et al., 2004,). In a subsequent animal study factors secreted by liver cyst epithelia were shown to promote endothelial cell proliferation and

hypoxic stimulus stimulates angiogenesis.

development (Brodsky et al., 2009).

**7. Angiogenic growth factors in ADPKD liver** 

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