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Review
. 2024 Oct 25:11:1471642.
doi: 10.3389/fmed.2024.1471642. eCollection 2024.

Exercise as a therapeutic approach to alleviate diabetic kidney disease: mechanisms, clinical evidence and potential exercise prescriptions

Rao Fan #  1 , Jianda Kong #  1 , Jiahao Zhang  1 , Lei Zhu  1
Affiliations
Review

Exercise as a therapeutic approach to alleviate diabetic kidney disease: mechanisms, clinical evidence and potential exercise prescriptions

Rao Fan et al. Front Med (Lausanne). .

Abstract

Diabetic kidney disease (DKD) is a global and severe complication that imposes a significant burden on individual health, families, and society. Currently, the main treatment approaches for DKD include medication, blood glucose control, protein-restricted diet, and blood pressure management, all of which have certain limitations. Exercise, as a non-pharmacological intervention, has attracted increasing attention. This review introduces the mechanisms and clinical evidence of exercise on DKD, and proposes potential exercise prescriptions. Exercise can improve blood glucose stability related to DKD and the renin-angiotensin-aldosterone system (RAAS), reduce renal oxidative stress and inflammation, enhance the crosstalk between muscle and kidneys, and improve endothelial cell function. These mechanisms contribute to the comprehensive improvement of DKD. Compared to traditional treatment methods, exercise has several advantages, including safety, effectiveness, and no significant side effects. It can be used as an adjunct therapy to medication, blood glucose control, protein-restricted diet, and blood pressure management. Despite the evident benefits of exercise in DKD management, there is still a lack of large-scale, long-term randomized controlled trials to provide more evidence and develop exercise guidelines for DKD. Healthcare professionals should actively encourage exercise in DKD patients and develop personalized exercise plans based on individual circumstances.

Keywords: RAAS; blood glucose stability; diabetic kidney disease; endothelial cell function; exercise; inflammation; musclekidney interaction; oxidative stress.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Pathogenesis of diabetic kidney disease (DKD). This figure illustrates the multiple pathogenic mechanisms of hyperglycemia in the development of diabetic kidney disease (DKD). Hyperglycemia, through insulin resistance, leads to reduced glucose uptake, activating various pathways, including the aldose reductase (AR) pathway, PI3K/AKT pathway, and mammalian target of rapamycin complex 1 (mTORC1) pathway. These pathways contribute to lipid metabolism disorders, mitochondrial dysfunction, and increased reactive oxygen species (ROS) production. These metabolic changes further result in diminished antioxidant defense capacity and enhanced extracellular matrix (ECM) synthesis, ultimately leading to glomerulosclerosis, renal fibrosis, and tubulointerstitial fibrosis. Activation of the renin-angiotensin-aldosterone system (RAAS) increases glomerular pressure and glomerular filtration rate (GFR), exacerbating kidney damage. Additionally, the accumulation of advanced glycation end products (AGEs) through crosslinking with collagen and elastin activates the nuclear factor-kappa B (NF-κB) and protein kinase C (PKC) pathways, driving inflammatory responses. These complex mechanisms collectively promote the onset and progression of diabetic kidney disease.
Figure 2
Figure 2
Mechanisms of the benefits of exercise on DKD. Figure 1 illustrates how exercise affects various pathways and axes related to diabetic kidney disease (DKD). Key pathways and molecules involved include the AMP-activated protein kinase (AMPK) pathway, mammalian target of rapamycin (mTOR) pathway, calcium/calmodulin-dependent protein kinase II (CaMKII) pathway, and the insulin receptor substrate 1/phosphoinositide 3-kinase/protein kinase B/glucose transporter type 4 (IRS1/PI3-K/AKT/GLUT4) pathway. It also highlights the role of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase (GSH-Px), interleukins IL-6 and IL-10, inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and transforming growth factor beta (TGF-β). The renin-angiotensin-aldosterone system (RAAS) is also depicted, with specific focus on the angiotensin-converting enzyme 2/angiotensin II/angiotensin II receptor type 1 (ACE/Ang II/AT1R) axis and the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/Mas) axis. Additionally, the nitric oxide synthase (NOS) and AMP-activated protein kinase/microRNA-181b (AMPK/miR-181b) axis are mentioned. The image further addresses the roles of transforming growth factor beta 1 (TGF-β1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and diabetic kidney disease (DKD).
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