A Boolean Model of Microvascular Rarefaction to Predict Renal Outcomes in Renovascular Disease

Abstract

Renal microvascular (MV) rarefaction, a hallmark of renovascular disease (RVD), associates with decreased renal vascular endothelial growth factor (VEGF) and progressive renal damage. We designed a novel bioengineered fusion of an elastin‐like polypeptide (ELP) with VEGF, and demonstrated that ELP‐VEGF therapy decreases MV rarefaction, improves renal function, and reduces renal injury in RVD. Renal angioplasty (PTRA) of a stenotic kidney is a frequently used treatment in RVD that often does not ameliorate renal injury. We thus aimed to create a Boolean model of MV rarefaction to predict the renal outcomes of an RVD kidney after ELP‐VEGF therapy following PTRA.We first created a Boolean model with 20 factors known to be involved in MV rarefaction and progression of renal injury in RVD (assuming each to be either totally present/active or totally absent/inactive) to predict the possible pathophysiological states and outcomes after treatments. The model predicts that MV rarefaction and fibrosis remain active following PTRA, driven by a feed‐forward cycle of inflammation and oxidative stress leading to glomerulosclerosis and fibrosis (Figure). When ELP‐VEGF therapy followed PTRA in the simulation, MV rarefaction, glomerulosclerosis, and fibrosis were inactivated. The model predicted that injurious processes driving progressive renal deterioration are decreased only with ELP‐VEGF therapy following PTRA.We next performed in vivo studies. RVD was induced by renal artery stenosis in 12 pigs fed a high‐cholesterol diet. Six weeks later, single‐kidney blood flow (RBF) and filtration (GFR) were quantified in vivo using multi‐detector CT, then pigs were randomized to either PTRA (RVD+PTRA, n=6) or PTRA followed by single intra‐renal injection of ELP‐VEGF (RVD+PTRA+ELP‐VEGF, n=7). Pigs were observed for 4 additional weeks; in vivo CT studies were repeated, then pigs euthanized and ex vivo renal micro‐CT quantification and fibrosis determined. Administration of ELP‐VEGF following PTRA improved RBF, GFR, MV density, and fibrosis more efficiently than PTRA alone.ConclusionThe Boolean model predicted the in vivo/ex vivo data and confirmed pathological mechanisms and the key role of MV damage in renal injury progression. Our results may support the use of Boolean simulations to predict renal outcomes after treatments. Furthermore, this study unravels a simple but useful tool that may help to design, confirm, or deny pre‐clinical studies and predict therapeutic effects.Support or Funding InformationAHA 18490005 (ARC), Intramural Research Support Program (IRSP) grant from UMMC (ARC), and PO1 HL 51971 (WAP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.