**9. Serum levels of angiogenic growth factors correlate with renal and cardiac disease severity in ADPKD**

Further evidence to support a role of angiogenic growth factors in the complications of ADPKD stems from our study in children and young adults (Reed et al., 2011). Measurement of VEGF, Ang-1 and Ang-2 in 71 children and young adults with ADPKD demonstrated strong correlations between log10 VEGF and both log10 total kidney volume and eGFR. (Table 3). In adult ADPKD patients no relationship between log10VEGF and total renal volume was found (N= 33). However, in adults there was a significant negative relationship between serum Ang-2 levels and eGFR (N = 85, p = 0. 04) that was not found in children and young adults. This indicates that VEGF may play a more significant role early in ADPKD, while Ang-2 may play a role in the progression of renal injury later in disease.


Table 3. Relationship of VEGF, Ang-1 and Ang-2 with renal structure and function.

Angiogenesis and the Pathogenesis of Autosomal Dominant Polycystic Kidney Disease 103

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

In this chapter we have presented evidence that angiogenesis may be an important factor in the pathogenesis of ADPKD. We have highlighted the similarities between cyst growth and growth of a benign tumour. Significantly, as has been demonstrated in other disease conditions circulating angiogenic growth factor levels are abnormally elevated even early in ADPKD and may indicate the severity of underlying renal and cardiac disease. Lastly, the benefits of anti-angiogenic therapies which target restoration of angiogenic growth factor balance remain to be determined in ADPKD but may hold future therapeutic promise.

This research was supported by Grant numbers M01RR00051, M01RR00069, the General Research Centers Program, National Center for Research Resources (NCRR/NIH; by NCRR/NIH Colorado CTSI Grant number UL1RR025780, by Grant DK34039 form NIH (NIDDK) and by the Zell Family Foundation. The content of this publication are the authors

Amura, C.R., Brodsky, K.S., Groff, R., Gattone, V.H., Voelkel, N.F. & Doctor, R.B. (2007)

VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice. *Am. J. Physiol. Cell. Physiol.,* Vol.293, No.1, (July 2007) pp. C419-428, ISSN 0363-6143 Ardelt, A,A,, McCullough, L.D., Korach, K.S., Wang, M.M., Munzenmaier, D.H. & Hurn,

P.D. (2005) Estradiol regulates angiopoietin-1 mRNA expression through estrogen

sole responsibility and do not necessarily represent the official NIH views.

angiogenic growth factors in progression of ADPKD.

**11. Conclusion** 

**12. Acknowledgment** 

**13. References** 

We have demonstrated significant positive correlations between LVMI and Ang-1 and VEGF in young subjects with ADPKD as shown in table 4 (Reed, et al., 2011). The relationship between LVMI and serum VEGF was apparent even in the absence of overt hypertension. This is of particular relevance as patients with ADPKD are at an increased risk for left ventricular hypertrophy (LVH) (Chapman et al., 1997). Similarly, in 33 adults a near significant relationship between LVMI and Ang-1 was observed. No relationship between VEGF and LVM was apparent in adults. However, there was a significant relationship between Log10 Ang-1/Ang-2 and LVM. As Ang-2 has been reported to be both pro-angiogenic or promote vascular regression dependent upon the presence or absence of VEGF (Holash et al., 1999; Lobov et al., 2002) assessment of the Ang-1/Ang-2 ratio may be biologically relevant. Thus, angiogenic growth factor levels may help identify children at risk for cardiovascular complications. This is important because cardiac MRI and/or echocardiography are not routinely performed on young patients with ADPKD.


Table 4. Relationship between VEGF, Ang1 and Ang-1/Ang-2 with Cardiac Structure.
