Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity

Abstract

Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular and renal diseases. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity. Summary and Key Message: Microvascular (MV) disease plays a pivotal role in progressive kidney injury from different etiologies such as hypertension, diabetes, and atherosclerosis, which are all important consequences of chronic obesity. The MV networks are anatomical units that are closely adapted to specific functions of nutrition and removal of waste in every organ. Damage of the small vessels in several tissues and organs has been reported in obesity and may increase cardio-renal risk. However, the mechanisms by which obesity and its attendant cardiovascular and metabolic consequences interact to cause renal MV injury and chronic kidney disease are still unclear, although substantial progress has been made in recent years. This review addresses potential mechanisms and consequences of obesity-induced renal MV injury as well as current treatments that may provide protection of the renal microcirculation and slow progressive kidney injury in obesity.

Figure 1

Top. Representative renal cross sections from adult lean and obese Zucker rats (LZR and OZR, respectively) showing inflammatory infiltrates, and quantification (percent of ED-1 + macrophages). Middle. Representative 3D micro-CT reconstruction of the renal microvasculature, and quantification of the renal fibrosis in adult LZR and OZR. Bottom: Representative bar graphs showing proteinuria and glomerular filtration rate (GFR) from adult LZR and OZR. Increased renal microvascular density in OZR was accompanied by increased inflammation, renal dysfunction and injury, suggesting pathological neovascularization. Grey bars: LZR, black bars: OZR. *p<0.05 vs. LZR. Reproduced and modified from Iliescu R. and Chade A.R., Microcirculation (2010) 17, 250–258.

Figure 2

Schematic illustration of the potential mechanisms of obesity-induced renal injury. Multiple injurious pathways for the kidney are activated by direct effects of obesity and visceral fat, leading to a progressive deterioration of renal function, microvascular rarefaction in the glomerular and peritubular compartments, and consequent development of progressive renal dysfunction and injury. Abbreviations: SNS, sympathetic nervous system; RAAS, renin-angiotensin aldosterone system; GFR, glomerular filtration rate; TNF, tumor necrosis factor; NFkB, nuclear factor kappa B; IL, interleukins; MCP-1, monocyte-chemoattractant protein-1; TGF, transforming growth factor; CTGF, connective tissue growth factor; FGF, fibroblast growth factor; TIMPs, tissue inhibitors of metalloproteinases; MMPs, matrix metalloproteinases.