An update on renal tubular injury as related to glycolipid metabolism in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes, which can result in end-stage renal disease (ESRD). As the main site of renal reabsorption and its exposed environment, renal tubules can be damaged by various factors. Recent studies have shown that renal tubular epithelial cells (RTECs) injury plays an important role in the occurrence and progression of DKD. The glycolipid metabolism disorders are a vital factor contributing to RTECs injury, which in turn affects the progression of DKD. Abnormal glucose and lipid metabolism can cause oxidative stress, mitochondrial damage, cell apoptosis and lipid accumulation, which can cause RTECs injury. Therefore, this review describes the main pathological mechanism of the injury caused by glycolipid metabolism and the corresponding therapeutic drugs in the clinical treatment of DKD.

Keywords: diabetic kidney disease; glucose metabolism; lipid metabolism; renal tubular epithelial cells; therapeutic medications.

FIGURE 1

Renal tubular injury in the development of diabetic kidney disease. Glucolipid imbalance can trigger renal tubulointerstitial fibrosis, hypertrophy, injury and apoptosis, leading to DKD and eventually ESRD. RTECs, renal tubular epithelial cells; DKD, diabetic kidney disease; ESRD, end-stage renal disease.

FIGURE 2

Mechanisms of RTECs injury by disorders of glycolipid metabolism. Elevated glucose levels induce oxidative stress, endoplasmic reticulum (ER) stress, inflammatory activation, and cellular apoptosis. Specifically, oxidative stress promotes ROS generation, which synergizes with ER stress to disrupt mitochondrial integrity, thereby exacerbating RTEC injury. Concurrently, hyperlipidemia and excessive EFD exacerbate lipid toxicity, directly triggering oxidative stress, mitochondrial dysfunction, and inflammatory cascades, ultimately leading to RTEC apoptosis and tubular damage. EFD, ectopic fat deposition; ER, endoplasmic reticulum; ROS, reactive oxygen species; RTECs, renal tubular epithelial cells; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; NF-κB, nuclear factor κB; IL-1β, interleukin-1beta; IL-6, interleukin-6; IL-18, interleukin-18; TNF-α, tumor necrosis factor α.

FIGURE 3

Mechanism of reducing renal tubule injury with typical hypoglycemic drugs. Metformin exerts its protective effects on RTECs by activating the AMPK pathway and suppressing HIF-1α expression, thereby mitigating oxidative stress, inflammation, ER stress, mitochondrial dysfunction, apoptosis, and EMT. Similarly, GLP-1RAs alleviate lipid toxicity in RTECs by inhibiting lipogenesis and enhancing fatty acid oxidation, which reduces EFD and associated cellular injury. Furthermore, both DPP-4i and SGLT2i attenuate renal cell necrosis and inflammation, delaying DKD progression through modulation of HIF-1α signaling. Additionally, DPP-4i suppresses NLRP3 inflammasome activation, thereby reducing tubulointerstitial fibrosis (TIF) and further preserving renal function. TZDs protects RTECs by inhibiting inflammatory cytokines. EFD, Ectopic fat deposition; ER, Endoplasmic reticulum; EMT, Epithelial-mesenchymal transition; TIF, Tubulointerstitial fibrosis; GLP-1RA, GLP-1 receptor agonists; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; IL-1β, interleukin-1beta; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; HIF-1α, hypoxia inducible factor-1α; HIF-2α, hypoxia inducible factor-2α; SIRT1, silent information regulator family protein 1; AMPK, adenosine 5′-monophosphate-activated protein kinase; NRF2, nuclear factor-erythroid 2-related factor 2; TIF, tubulointerstitial fibrosis; TZDs, Thiazolidinediones.

FIGURE 4

Mechanism of reducing renal tubule injury with typical lipid-lowering drugs. Statins attenuate RTEC injury by downregulating NF-κB signaling, thereby suppressing inflammatory responses. Fibrates exert reno-protective effects through dual mechanisms: directly reducing TG synthesis and upregulating PPARα to counteract renal fibrosis and apoptosis. Ezetimibe mitigates RTEC damage by inhibiting lipid peroxidation and enhancing renal antioxidant enzyme activity. Similarly, omega-3 fatty acids protect RTECs by alleviating ER stress and reducing apoptotic cell death. RTECs, renal tubular epithelial cells; NF-κB, nuclear factor κB; PPAR-α, peroxisome proliferators-activated receptors; ER, Endoplasmic reticulum.

FIGURE 5

Graphic summary: Mechanisms of glycolipid metabolism disorders leading to DKD and clinical drugs. This figure provides a comprehensive overview of the hypoglycemic and lipid-lowering agents discussed in this review, highlighting their mechanisms in mitigating DKD-associated tubular injury. RTECs, renal tubular epithelial cells; DKD, diabetic kidney disease; ESRD, end-stage renal disease; EFD, ectopic fat deposition; ER, endoplasmic reticulum; ROS, reactive oxygen species; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; NF-κB, nuclear factor κB; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; EMT, epithelial-mesenchymal transition; HIF-1α, hypoxia inducible factor-1α; HIF-2α, hypoxia inducible factor-2α; AMPK, adenosine 5′-monophosphate-activated protein kinase; PPAR-α, peroxisome proliferators-activated receptors; PI3K/AKT, phosphatidylinositide 3-kinases/protein kinase B or PKB.