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Review
. 2020 Jul;245(13):1142-1154.
doi: 10.1177/1535370220928986. Epub 2020 Jun 2.

Influence of exercise training on diabetic kidney disease: A brief physiological approach

Liliany Souza de Brito Amaral  1 , Cláudia Silva Souza  2 , Hernando Nascimento Lima  1 , Telma de Jesus Soares  1
Affiliations
Review

Influence of exercise training on diabetic kidney disease: A brief physiological approach

Liliany Souza de Brito Amaral et al. Exp Biol Med (Maywood). 2020 Jul.

Abstract

Diabetic kidney disease (DKD) is associated with increased mortality in diabetic patients and has a negative impact on public health. The identification of potential therapies that help the management of DKD can contribute to the improvement of health and quality of life of patients. Thus, this paper is timely and relevant because, in addition to presenting a concise review of the pathogenesis and major pathophysiological mechanisms of DKD, it addresses the most recent findings on the impact of exercise training on this disease. Thus, since non-pharmacological interventions have gained increasing attention in the fight against chronic diseases, this paper appears as an important tool to increase knowledge and stimulate innovative research on the impact of exercise on kidney disease.

Keywords: Diabetes mellitus; diabetic kidney disease; exercise training.

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Figures

Figure 1.
Figure 1.
Overview of the pathophysiological mechanisms of diabetic kidney disease. Metabolic changes are related to AGEs formation and activation of the polyol and PKC pathways. These pathways result in the generation of ROS and consequent reduction of NO levels. The NO when reduced exacerbates TGF-β1 bioactivity. ROS and PKC activate NF-кB, which, in turn, increases the expression of TGF-β1 and CCL2. The CCL2 mediates macrophage infiltration, while TGF-β1 increases fibronectin and other ECM proteins (type I, III, IV collagens) deposition. Infiltrated macrophages express pro-inflammatory cytokines such as IL-1, IL-6, IL-18, TNF-α and increase the expression of adhesion molecules that are responsible for facilitating the macrophages infiltration in the diabetic kidney. The TNF-α is also responsible for activating NF-кB. On the other hand, hemodynamic changes are related to AII expression from mesangial cells and shear stress, leading to proteinuria, which directly causes NF-кB activation. Glomerular hypertension and consequent shear stress stimulate local production of AII, which increase NF-кB activation and consequently inflammation. Abbreviations: AGE: advanced glycation end-product; PKC: protein kinase C; NO: nitric oxide; TGF-β1: transforming growth factor-beta 1; ROS: reactive oxygen species; CCL2: C-C motif chemokine ligand 2; ECM: extracellular matrix; IL: interleukin; TNF-α: tumor necrosis factor alpha; NF-кB: nuclear factor-kappa B; AII: angiotensin II. (A color version of this figure is available in the online journal.)
Figure 2.
Figure 2.
Overview of the exercise training mechanisms attenuating the metabolic and hemodynamic changes of diabetic kidney disease. Exercise promotes metabolic and hemodynamic improvements. Activation of the SIRT1-PGC pathway results in improved mitochondrial function and consequent reduction in muscle catabolism. Glucose uptake is increased by exercise by activating AMPK and insulin-mediated pathways to reduce hyperglycemia, formation of AGEs, and consequently reduction of ROS. Activation of the P2X7 receptor reduces lipid peroxidation and thus attenuates the formation of ROS. Activation of Nfr2 increases the expression of antioxidant enzymes and thus reduces the formation of ROS. Increased cardiac output and renal vasoconstriction provide shear stress, which induces NO production. Elevated NO levels are related to TGF-β1, ECM protein deposition, and fibrosis reductions. Exercise provides angiogenesis and endothelial function by NO, VEGF, eNOS, and SDF-1 production. Abbreviations: SIRT1-PGC: sirtuin 1-gamma coactivator 1-α; AMPK: AMP-activated protein kinase; AGEs: advanced glycation end-products; ROS: reactive oxygen species; Nfr2: nuclear factor erythroid 2-related factor 2; NO: oxide nitric; TGF-β1: transforming growth factor-beta 1; ECM: extracellular matrix; VEGF: vascular endothelial growth factor; eNOS: endothelial nitric oxide synthase; SDF-1: stromal cell-derived factor-1α. (A color version of this figure is available in the online journal.)
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