SAT-126 PROGRESSION OF RENAL MICROVASCULAR ABNORMALITIES AND THE EFFECT OF SIROLIMUS ON ANGIOGENESIS IN EXPERIMENTAL POLYCYSTIC KIDNEY DISEASE

Abstract

Polycystic kidney disease (PKD) is the most common genetic cause of kidney failure, and is characterized by the development of hundreds of fluid-filled cysts in the kidney. The enlargement of these cysts leads to interstitial fibrosis, loss of normal renal parenchyma, and eventually end-stage renal disease (ESRD). Progressive cyst growth is also accompanied by neoangiogenesis and the loss of normal renal microvasculature. The aim of this study was to determine the progression of renal microvascular abnormalities in PKD, and whether this is altered by sirolimus, a cyst growth inhibitor with anti-angiogenic properties. Kidney sections from Lewis Polycystic Kidney (LPK) rats and juvenile cystic kidney (jck) mice were examined at the early (week 1 LPK; week 4 jck), established (week 3 to 12 LPK; week 8 jck) and end-stage phases of cystic renal disease (week 24 LPK; week 12 jck). Angiogenesis and peritubular capillary loss were assessed by immunohistology using antibodies against endothelial cells (RECA-1 for LPK rats and CD34 for jck mice). In addition, LPK rats and jck mice were treated with sirolimus or vehicle during the established phase of disease (starting at 9 weeks of age in LPK rats and 4 weeks of age in jck mice), to monitor its effect on kidney weight, cyst area, and renal vasculature. Angiogenesis was evident during the established phase of cystic renal disease in both LPK rats and jck mice, and persisted with progression. In LPK rats, peritubular capillary loss occurred rapidly during the early cystic stage, whereas in jck mice this loss was only evident at the end-stage cystic phase. Treatment with sirolimus demonstrated a slight but significant decrease in percentage two kidney weight to total body weight (2KW/TBW; 10.5%) compared to vehicle in LPK rats, but this was not observed in the jck mice. Sirolimus treatment did not alter angiogenesis or the loss of peritubular capillaries in either model. These data indicate that angiogenesis is an early feature of cystic renal disease, persists over time, and is accompanied by the loss of peritubular capillaries. Sirolimus did not alter angiogenesis in LPK rats or jck mice when administered in the established phase of disease. Future studies could test treatment at earlier time points, or inhibitors of alternate pathways of angiogenesis could also be studied as a strategy to reduce neoangiogenesis and cyst progression in PKD.