Obesity-metabolic derangement preserves hemodynamics but promotes intrarenal adiposity and macrophage infiltration in swine renovascular disease

Abstract

Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean-RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood-oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MØ) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MØ, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MØ-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney.

Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats

“…Hyperleptinaemia is positively correlated with the degree of obesity (Ahima & Flier 2000, Tam et al 2012 and is also associated with increased TGFB1 production and collagen deposition leading to increased fibrosis in CKD (Wolf & Ziyadeh 1999, Briffa et al 2013. Previous studies have established that fibrotic markers including TGFB1, collagen IV and VEGFA are up-regulated in the kidney in obesity-related nephropathy (Jiang et al 2005, Cignarelli & Lamacchia 2007, Mathew et al 2011, Briffa et al 2013, Nolan et al 2013, Zhang et al 2013. Indeed, it has been shown that in lean transgenic mice that overexpress CB 1 , there is an increase in glomerular expression of VEGFA (Hsu et al 2014).…”

Angiotensin 1–7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity

“…Inflammation is also a key driver of diabetic nephropathy, and inflammation in adjacent perirenal adipose tissue exacerbates diabetic nephropathy (45). Adipose tissue shows increased adipocyte size, macrophage infiltration, and fibrosis in the setting of metabolic derangements (46,49). The perirenal adipose tissue from db/db mice showed a marked increase in inflammatory cells, concomitant with the increased adipocyte cross-sectional area and enhanced fibrosis in perirenal adipose tissue (Fig.…”

Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function

“…Fat measurement. Intra-abdominal adipose tissue was expressed as volume and fraction (21,22,39). With the use of Analyze, the attenuation range of subcutaneous fat tissue was used to automatically threshold the adipose tissue through the entire image.…”