Chronic kidney disease (CKD) universally associates with renal microvascular rarefaction and inflammation, but whether a link exists between these 2 processes is unclear. We designed a therapeutic construct of VEGF (vascular endothelial growth factor) fused to an ELP (elastin-like polypeptide) carrier and show that it improves renal function in experimental renovascular disease. We test the hypothesis that ELP-VEGF therapy will improve CKD, and that recovery will be driven by decreasing microvascular rarefaction partly via modulation of macrophage phenotype and inflammation. CKD was induced in 14 pigs, which were observed for 14 weeks. At 6 weeks, renal blood flow and filtration were quantified using multidetector computed tomography, and then pigs received single intrarenal ELP-VEGF or placebo (n=7 each). Renal function was quantified again 4 and 8 weeks later. Pigs were euthanized and renal microvascular density, angiogenic and inflammatory markers, fibrosis, macrophage infiltration, and phenotype were quantified. Loss of renal hemodynamics in CKD was progressively recovered by ELP-VEGF therapy, accompanied by improved renal microvascular density, fibrosis, and expression of inflammatory mediators. Although renal macrophage infiltration was similar in both CKD groups, ELP-VEGF therapy distinctly shifted their phenotype from proinflammatory M1 to VEGF-expressing M2. Our study unravels potential mechanisms and feasibility of a new strategy to offset progression of CKD using drug-delivery technologies. The results indicate that renal recovery after ELP-VEGF therapy was largely driven by modulation of renal macrophages toward VEGF-expressing M2 phenotype, restoring VEGF signaling and sustaining improvement of renal function and microvascular integrity in CKD.

Macrophages are heterogenous cells of the innate immune system that can fluidly modulate their phenotype to respond to their local microenvironment. They are found throughout the renal compartments, where they contribute to homeostasis and function. However, renal injury activates molecular pathways that initially stimulate differentiation of macrophages into a proinflammatory M1 phenotype. Later in the course of healing, abundant apoptotic debris and anti-inflammatory cytokines induce the production of anti-inflammatory M2 macrophages, which contribute to tissue regeneration and repair. Thus, the dynamic balance of M1 and M2 populations may outline the burden of inflammation and process of tissue repair that define renal outcomes, which has been the impetus for therapeutic efforts targeting macrophages. This review will discuss the role of these phenotypes in the progression of chronic renal injury, potential pathogenic mechanisms, and the promise of macrophage-based therapeutic applications for chronic kidney disease.

Animal models of chronic kidney disease (CKD) are critical for understanding its pathophysiology and for therapeutic development. The cardiovascular and renal anatomy and physiology of the pig are virtually identical to humans. This study aimed to develop a novel translational model of CKD that mimics the pathological features of CKD in humans. CKD was induced in seven domestic pigs by bilateral renal artery stenosis and diet-induced dyslipidemia. Animals were observed for a total of 14 wk. Renal hemodynamics and function were quantified in vivo using multi-detector CT after 6, 10, and 14 wk of CKD. Urine and blood were collected at each time-point, and blood pressure was continuously measured (telemetry). After completion of in vivo studies, pigs were euthanized, kidneys were removed, and microvascular (MV) architecture (μCT), markers of renal injury, inflammation, and fibrosis were evaluated ex vivo. Additional pigs were used as controls ( n = 7). Renal blood flow and glomerular filtration were reduced by 50% in CKD, accompanied by hypertension and elevated plasma creatinine, albumin-to-creatinine ratio and increased urinary KIM-1 and NGAL, suggesting renal injury. Furthermore, 14 wk of CKD resulted in cortical and medullary MV remodeling and loss, inflammation, glomerulosclerosis, tubular atrophy, and tubule-interstitial fibrosis compared with controls. The current study characterizes a novel model of CKD that mimics several of the pathological features observed in human CKD, irrespective of the etiology. Current approaches only slow rather than halt CKD progression, and this novel model may offer a suitable platform for the development of new treatments in a translational fashion.