**10. Potential benefit of anti-angiogenic therapy in ADPKD**

VEGF receptor inhibition by SU-5416 has been shown to significantly reduce liver cyst burden in pkd2(WS25/-)mice (Amura et al., 2007). Likewise, studies in the cy/+ rat model of polycystic kidney disease demonstrated that treatment with ribozymes to block VEGFR-1 and VEGFR-2 mRNA expression resulted in decreased cyst burden in the kidney (Tao et al., 2007). Metalloproteinase inhibition by batimastat in the cy/+ rat model has also been shown to significantly reduce kidney weight and cyst number in treated animals compared to untreated animals (Obermuller et al., 2001).

Several inhibitors that either target VEGF directly such as bevacizumab or those such as sorafenib and sunitinib that target receptor tyrosine kinases including VEGFR's and platelet derived growth factor receptors have shown some success in cancer therapy. Indicating that these drugs may have a potential role in ADPKD therapy. However, there are several side effects associated with both of these drug classes including but not limited to hemorrhage, decreased wound healing and hypertension. Side effects are a significant consideration in relation to ADPKD therapy where drug use must potentially be continued for life. While most anti-angiogenic drugs are targeted towards cancer therapy, bosutinib a receptor tyrosine kinase inhibitor targeting the Src/Abl kinases which also reduces VEGF activity is currently in phase II clinical trial for ADPKD (NCT01233869).

In terms of other anti-angiogenic targets, there are several ongoing cancer clinical trials with Ang-1 or Ang-2 inhibitors. Depending on the outcome of these ongoinig trials these drugs may hold some promise for future ADPKD therapy. It is also relevant that there are many naturally occurring inhibitors of angiogenesis including angiostatin, endostatin, vasostatin, TIMPs, thrombospondins, tumstatin, prolactin (inhibits both basic fibroblast growth factor and VEGF), vasohibin-1 and sFlt1 which may also have benefit in ADPKD. The therapeutic effects of several endogenous angiogenesis inhibitors including angiostatin, endostatin, tumstatin, vasohibin-1, and the synthetic derivative of bacterial cytogenin, 1-(8-hydroxy-6 methoxy-1-oxo-1H-2-benzopyran-3-yl) proprionic acid (NM-3) have been examined in animal models of diabetic nephropathy as reviewed by Maeshima and Makino (Maeshima & Makino, 2010). These angiogenesis inhibitors have been shown to reduce renal hypertrophy/hyperfiltration and reduce albuminuria when administered during the early stages of disease (Zhang et al., 2006, Ichinose et al., 2005, Yamamoto et al., 2004, Nasu et al., 2009, Ichinose et al., 2006). However, no human studies have been performed to date. In animal models of non-diabetic renal disease angiostatin treatment has resulted in both beneficial anti-inflammatory effects while the anti-angiogenic reduction in peritubular capillaries may worsen tubular hypoxia (Mu et al., 2009). Thus, with progressive renal diseases including ADPKD angiogenic growth factors may both promote renal injury or protect from hypoxia by maintenance of the peritubular capillaries. While in the early stages of ADPKD therapeutic restoration of normal angiogenic factor balance may be more beneficial, later disease stages may need a different approach to ameliorate increasing renal hypoxia. However, further research is necessary to explore the potential disparate roles of angiogenic growth factors in progression of ADPKD.
