Cardiology Research and Practice hemodynamic and metabolic abnormalities. Many factors contribute to the increase in both glomerular ﬁltration rate (GFR) and rise in renal plasma ﬂow (RPF) observed in obese patients. The increased protein intake determines a rise in GFR [124]. Moreover, IR causes increase in the eﬀerent arteriolar pressure because the reduction of noradrenaline- induced eﬀerent arteriolar constriction by insulin action is blunted. Subsequently, the transcapillary pressure gradient increases resulting in hyperﬁltration [124]. Augmented ﬁltration determines microalbuminuria. Moreover, insulin stimulates the synthesis of IGF-1 and IGF-2, both promoting glomerular hypertrophy [122, 124]. The rapid and parallel increases in the prevalence of end-stage renal disease and obesity in the past two decades suggest that obesity may be a major risk for kidney disease through other mecha- nisms than diabetes and hypertension (see Figure 1) [125]. Additionally, obesity increases the risk of development of renal diseases from diﬀerent aetiologies, such as primary immunoglobulin A nephritis or unilateral nephrectomy [126, 127]. Whether weight loss, in the long term, can slow down the progression of renal damage or reverse it is unknown at the present time. In the short term, weight loss usually leads to reduction of the proteinuria. Antiproteinuric eﬀects of weight loss are also observed in obese patients with nephropathies due to other causes [126]. 7. Mechanisms of Vascular Damage in Obesity Abdominal obesity is well recognized as a major risk factor for CVD, but the underlying mechanisms of vascular damage in obesity remain poorly understood. One of the most important mechanisms by which obesity leads to the development of vascular diseases is the development of IR in skeletal muscle, adipose tissue, and liver. The adipose tissue excess, particularly visceral fat, is associated with a continuous production of mediators that impair insulin action in skeletal muscle, like free fatty acids (FFAs), and is associated with a decreased production of adiponectin, a mediator known to improve insulin sensitivity [128]. Plasminogen activator inhibitor-1 (PAI-1) is typically increased in the obesity/IR state and plays an important role in the genesis of vascular abnormalities [129]. In addition, obesity and IR are frequently associated with altered coagulation/ﬁbrinolysis. In combination, all of the above abnormalities create a state of constant and progressive damage to the vascular wall, manifested by a low-grade progressive inﬂammatory process [130]. Endothelial dys- function is deﬁned as paradoxical or inadequate endothelial- mediated vasodilation and is characterized by loss of balance between vasoconstrictors and vasodilators, increased oxida- tive stress, and elevated expression of proinﬂammatory and prothrombotic factors. Endothelial dysfunction is a fundamental initial step in the development and progression of atherosclerosis and has been considered an important event in the development of microvascular complications [130]. Adipose tissue can produce a signiﬁcant amount of compounds able to aﬀect endothelial function; the ability of adipokines to directly aﬀect vascular homeostasis may Visceral fat cells 5 Kidney ↓ Adiponectin Arterial vessel podocyte’s alteration ↑ Inﬂammatory adipokines Oxidative stress Potential interaction between early kidney disfunction and systemic oxidative stress Figure 1: Possible dynamic interactions between obesity, CKD, and CVD. The increase of visceral mass determines both decreased production of ADN and increased production of inﬂammatory adipokines which result in increased insulin resistance. represent an important mechanistic basis of vascular disease in patients with obesity. Central obesity is associated with increased levels of free fatty acid (FFA) that induces endothe- lial dysfunction by eﬀect of insulin-mediated vasodilatation in humans and by impairment of nitric oxide-independent mechanism mediated by reduction of potassium-mediated vasodilatation [131]. The increased levels of FFA from the more lipolytically active intra-abdominal adipocytes decreased insulin sensitivity through the intracellular insulin signaling [132]. Moreover, FFAs are capable of utilizing the innate immune receptor TLR4 to induce proinﬂammatory cytokine expression in macrophages and adipocytes. In particular, the TLR4 signaling appears to be required for a component of insulin resistance induced by FFAs in adipocytes and in vivo after lipid infusion and high-fat diets [133]. Moreover, TNF alpha overproduction in obesity medi- ates the increased endothelial permeability by activating NADPH oxidase [129] and also inhibits transcriptional, as well as posttranscriptional, eNOS gene expression an eﬀect that can account for the endothelial dysfunction. In obese patients, an increase in reactive oxygen species has been demonstrated and could be the link between the low-grade inﬂammation, platelet activation, and nitric oxide destruction. In IR and obesity, the dyslipidaemia is characterized by a diﬀerent composition and distribution of LDL choles- terol, resulting in an increased concentration of the more atherogenic small dense LDL. Small dense LDL particles can move through endothelial fenestrations, entering the suben- dothelial space where inﬂammation and transformation into plaque can occur [134]. Moreover, the ox-LDL is mostly taken up by macrophage scavenger receptors, rather than the normal LDL receptor pathway, thus inducing atherosclerosis.