Hypoxia-Induced Metabolic Reprogramming in the Renal Tubules of Patients with Diabetic Kidney Disease and the Associated Traditional Chinese Medicine Intervention Strategies
Year: 2025
Type: article
Abstract: INTRODUCTION Diabetic kidney disease (DKD) is both a major complication of diabetes mellitus and a leading cause of end-stage renal disease.[1] Earlier studies based on traditional Chinese medicine (TCM) focused on the glomerular injury as the primary site of the pathology of diabetic kidney disease (DKD),[2] although recent research has highlighted the significant role played by renal tubules in the progression of the disease.[3] Hypoxia, a common feature of the renal microenvironment in patients with DKD, has been shown to mediate the metabolic reprogramming in renal cells, particularly in renal tubular epithelial cells (TECs).[4] Some TCM compounds and formulas have been shown to enhance cell hypoxia tolerance, reduce local oxygen consumption, and regulate mitochondrial energy metabolism, indicating them to be potential agents for the overall regulation of the hypoxic environment in DKD.[5] In this paper, we highlighted the evolving understanding of DKD’s pathogenesis in terms of hypoxia-induced metabolic reprogramming and discuss the TCM intervention strategies (Chinese herbal decoctions, Chinese patent medicines, and Chinese medicinal compounds) for DKD that target this mechanism. FROM GLOMERULI TO TUBULES: THE CENTRAL FOCUS CONCERNING THE PATHOGENESIS OF DKD IS SHIFTING An innovative theoretical framework concerning the pathogenesis of DKD has recently been proposed, which the international nephrology community has termed “tubulocentric theory”.[6] This theory emphasizes the role of the renal tubular microenvironment and identifies it as the central site for DKD initiation. In patients with type 2 diabetes mellitus (T2DM) who exhibit microalbuminuria, severe tubular injury is frequently observed. Indeed, the incidence of such injury is significantly higher than that of classic glomerular structural abnormalities. This finding suggests that tubular lesions have independent predictive value with regard to DKD’s progression. In a study by Conway et al., the urinary kidney injury molecule-1 (uKIM-1)/creatinine (Cr) and urinary Glycoprotein nonmetastatic melanoma protein B (uGpnmb)/Cr ratios were found to be elevated in patients with incipient diabetic nephropathy due to T2DM, suggesting ongoing tubular injury. Both tubular biomarkers were correlated with the severity of proteinuria and a faster decline in renal function.[6] A three-year prospective intervention trial conducted by Nielsen et al. found that diabetes patients with high levels of urinary neutrophil gelatinase-associated lipocalin (NGAL) and KIM-1 exhibited a faster decline in the glomerular filtration rate, suggesting tubular damage is important for progression of DKD.[6] Molecular pathology research has also provided evidence regarding the pathogenesis of DKD, including mitochondrial dysfunction, metabolic imbalance, and fibrous progression in TECs. Moreover, the epithelium of the renal tubules undergoes necrosis and shedding, while defects and exfoliation areas appear on the walls of the renal tubules. The lumen of the tubules can also directly communicate with the renal interstitium, causing the urine originally in the lumen to reflux and spread into the renal interstitium, resulting in renal interstitial edema, compression of nephrons, aggravation of renal ischemia, and a further reduction in the glomerular filtration rate.[7] Thus, both the American Diabetes Association and the Chinese Diabetes Association recommend that markers of renal tubular injury, such as plasma KIM-1, urine NGAL, cystatin C, and liver fatty acid binding protein (L-FABP), be recognized as important reference indicators of DKD.[8,9] HYPOXIA-INDUCED METABOLIC REPROGRAMMING: A NOVEL MECHANISM OF TUBULAR INJURY IN DKD Patients with diabetes experience local hypoxia due to vascular damage and high energy demands, with the renal tubules being particularly affected. Renal tubular cells, especially those located in the proximal tubules, exhibit high metabolic activity and require substantial energy for reabsorption, resulting in a high oxygen demand (Proximal tubular cells isolated from diabetic rats displayed increased transport and ouabain-inhibitable O2 consumption with 25 nmol/mg protein/min compared to the corresponding controls with 16 nmol/mg protein/min).[10] Hyperglycemia further increases the reabsorption load on the tubules, leading to higher oxygen consumption. Moreover, mitochondrial dysfunction in tubular cells impairs oxygen utilization. Collectively, these factors render the tubules more susceptible to damage under hypoxic conditions (A drop below 20 mmHg).[11] Renal TECs exhibit high metabolic activity, and their metabolic patterns undergo significant changes during hypoxia. These changes are collectively termed “metabolic reprogramming”. More specifically, the changes manifest as (1) increased glycolytic flux, (2) inhibited fatty acid oxidation (FAO), and (3) imbalanced mitochondrial function with reduced oxidative phosphorylation efficiency.[12] A diagram showing the specific pattern of these changes is shown in Figure 1. Normally, TECs rely primarily on FAO, which produces large amounts of adenosine triphosphate (ATP) to meet the physiological demands. Non-adipocyte fatty acid uptake occurs via transmembrane proteins, with the key proteins including CD36, fatty acid transport proteins, and fatty acid binding proteins. Subsequently, carnitine palmitoyltransferase 1 (CPT-1d) catalyzes fatty acid transfer into the mitochondria, which enables FAO. In turn, FAO generates acetyl-CoA, which then participates in the tricarboxylic acid (TCA) cycle.[13] This cycle provides energy for the kidneys. In DKD, hypoxia promotes the transition of the metabolic morphology of FAO into glycolysis, simultaneously inhibiting mitochondrial function, reducing the activity of the TCA cycle, and generating a large amount of metabolic wastes, including reactive oxygen species.Figure 1.: Diagram of the hypoxia-induced metabolic reprogramming pattern in the TECs of patients with DKD. In the TECs of patients with DKD, chronic hypoxia-specific metabolic reprogramming shifts the cellular metabolism from FAO to glycolysis. Glycolysis, using glucose as a substrate, generates acetyl-CoA via pyruvate metabolism to participate in the TCA cycle, with lactate production occurring en route. FAO, using free fatty acids as substrates, also enters the TCA cycle via acetyl-CoA with acetic acid as an auxiliary. This metabolic shift disrupts the TCA cycle, generating reactive oxygen species as by-products. Combined with mitochondrial dysfunction, this causes oxidative stress damage and epithelial–mesenchymal transition. This process releases inflammatory mediators, promotes inflammatory cell infiltration, activates fibrotic factors and fibroblasts, impedes normal cell proliferation, and exacerbates the local DKD pathology. DKD, diabetic kidney disease; FAO, fatty acid oxidation; TCA, tricarboxylic acid; TECs, tubular epithelial cells; ATP, adenosine triphosphate; ROS, reactive oxygen species; α-KG, α-Ketoglutarate; BCAA, Branched-Chain Amino Acids. Hypoxia can also inhibit autophagy in cells, leading to the further accumulation of reactive oxygen species, which could have been cleared. This results in the release of fibrogenic factors into renal TECs, the activation of fibroblasts, the recruitment of inflammatory cells, and the transdifferentiation of epithelial cells into fibroblasts, thereby exacerbating the damage and fibrosis associated with DKD.[14] Moreover, hypoxia constitutes a profibrotic stimulus for tubular cells. It upregulates the transforming factor β1 (TGF-β1) expression in TECs, thereby reducing the matrix metalloproteinase (MMP) expression and increasing the tissue inhibitor of metalloproteinase (TIMP) expression in the kidney. These changes alter the metabolism of fibroblasts and the extracellular matrix in renal intrinsic cells, which leads to renal interstitial fibrosis. This fibrosis, in turn, impairs oxygen delivery, worsening tubular hypoxia and creating a vicious cycle.[15] Eventually, tubulointerstitial fibrosis compromises the local blood flow and induces tubular ischemic injury. Hypoxia-inducible factor 1-alpha (HIF-1α) is the key upstream molecule. It serves as a direct transcriptional activator of the glucose transporters glucose transporter 1 and glucose transporter 3, as well as of almost all the glycolytic enzymes, including phosphoglycerate kinase 1, glucose-6 phosphoisomerase, phosphofructokinase-1, and lactate dehydrogenase. However, damage to HIF-1α can lead to the activation of metabolic reprogramming, exacerbating cellular oxidative stress and inflammatory responses. Under normoxia, the HIF-1α subunit is continuously produced in the cytoplasm and undergoes rapid degradation. Hypoxia stabilizes the HIF-1α expression, which then suppresses oxidative phosphorylation. This directs cells toward ATP production via glycolysis. HIF-1α plays a critical protective role in relation to ischemic renal injury and enables tissue adaptation to hypoxia.[16] In the event of hyperglycemia, methylglyoxal accumulates, which reduces the HIF-1α transcriptional activity. The nuclear import efficiency of hypoxia-induced HIF-1α is reduced. The HIF-1α-mediated adaptive responses to hypoxia are consequently impaired in patients with diabetes. This impairment exacerbates kidney injury. In vitro, HIF-1α knockout induces TEC death in response to hypoxia-reoxygenation, while in vivo, HIF-1α knockout worsens tissue damage and renal dysfunction. This has been found to occur during reperfusion following ischemic injury in rats.[17] ALLEVIATING HYPOXIA AND REVERSING METABOLIC REPROGRAMMING: A HOLISTIC TCM STRATEGY FOR ADDRESSING DKD TCM attributes the pathogenesis of DKD to “micro-stasis” formation.[18] This pathology correlates with dual Qi and Yin deficiency, as well as with blood stasis in the collaterals. The overall disease evolution presents a pattern of “root deficiency coupled with branch excess”, which means that the fundamental debility of Qi and Yin allows secondary pathogenic factors—here, stagnant blood or “micro-stasis”—to accumulate as the overactive branch in TCM terms. Several TCM formulas can alleviate hypoxia and reverse metabolic reprogramming, thereby exerting renal protective effects. For example, Zhenwu decoction modulates the hypoxia microenvironment and consequently alleviates renal fibrosis.[19] Moreover, the Tangshen formula has been found to significantly improve autophagy, enhance FAO, and ultimately, alleviate DKD-related renal damage in a db/db mouse model of type 2 DKD.[20] An overview of additional studies concerning TCM and hypoxia-induced metabolic reprogramming is provided in Table 1. Table 1 - Overview of studies on the renal protective effects of TCM in terms of hypoxia-induced metabolic reprogramming Title Author, year Model Intervention Effect on hypoxia-induced metabolic reprogramming Phenotypic results Reference (DOI) The extract of Rhodiolae Crenulatae Radix et Rhizoma induces the accumulation of HIF-1α via blocking the degradation pathway in cultured kidney fibroblasts Zheng KY, 2011 Cultured kidney fibroblasts (HEK293T) Extract of Rhodiolae Crenulatae Radix et Rhizoma Increased HIF-1α protein via the reduction of HIF-1α degradation Induced production of erythropoietin doi: 10.1055/s-0030-1250627 Shen Shuai II Recipe attenuates renal fibrosis in chronic kidney disease by improving hypoxia-induced the imbalance of mitochondrial dynamics via PGC-1α activation Wang M, 2022 5/6 A/I surgery-induced RIF and intrarenal hypoxia in rats Shen Shuai II Recipe Improved the mitochondrial dynamics, oxidative metabolism, and mitochondrial reactive oxygen species under hypoxia Decreased the urine protein level and alleviated the degree of renal interstitial fibrosis doi: 10.1016/j. phymed.2022.153947 Shen Shuai II Recipe inhibits hypoxia-induced glycolysis by preserving mitochondrial dynamics to attenuate kidney fibrosis Wang L, 2023 5/6 A/I operation in CKD rats and hypoxia-treated NRK-52E cells Shen Shuai II Recipe Reduced glycolysis and improved the mitochondrial dynamics and membrane potential Improved the fibrotic phenotype doi: 10.1016/j.jep.2023.116271 JinChan YiShen TongLuo Formula ameliorate mitochondrial dysfunction and apoptosis in diabetic nephropathy through the HIF-1α-PINK1-Parkin pathway Zheng QY, 2024 Unilateral nephrectomy combined with low-dose streptozotocin intraperitoneally injected in a DN rat model and HG- and hypoxia-induced HK-2 cells Jin Chan Yi Shen Tong Luo Formula Promoted the accumulation of HIF-1α, increased the mitochondrial membrane potential, improved the activities of mitochondrial respiratory chain complexes I, III, and IV as well as the morphology of the mitochondria Decreased albuminuria, serum Cr, blood urea nitrogen, and uric acid levels and increased Cr clearance levels doi: 10.1016/j.jep.2024.117863 Shen-Shuai-II-Recipe inhibits tubular inflammation by PPARα-mediated fatty acid oxidation to attenuate fibroblast activation in fibrotic kidneys Wang M, 2024 CKD model rats and NRK-52E cells Shen Shuai II Recipe Promoted restoration of PPARα-mediated FAO and improved lipid accumulation Suppressed the inflammatory response and inhibited renal fibroblast activation doi: 10.1016/j.phymed.2024.155450 Ferulic Acid Inhibits Partial Epithelial-Mesenchymal Transition in Renal Tubular Epithelial Cells and Mitigates Renal Interstitial Fibrosis by Regulating the HIF-1α/Twist Signaling Pathwa Xu L, 2025 5/6 nephrectomy-induced chronic renal failure rat Ferulic Acid Reduced HIF-1α and α-SMA expression, decreased renal oxygen consumption, and inhibited partial epithelial-mesenchymal transition Improved renal function and attenuated fibrosis in kidney tissues doi: 10.1111/cbdd.70133 Mechanism of Zhenwu Decoction modulating TLR4/NF-κB/HIF-1α loop through miR-451 to delay renal fibrosis in type 2 CRS Xu X, 2024 Ligation of the left anterior descending branch of the coronary artery + 3/4 nephrectomy for type 2 cardiorenal syndrome rats Zhen Wu Decoction Inhibited the expression of HIF-1α proteins and genes, downregulated the expression of inflammatory factors and fibrosis-related factors Scr, BUN, and NT-proBNP, and urine protein, attenuated renal interstitial fibrosis, and improved tubular swelling doi: 10.1016/j.phymed. 2024.155632 Tangshen formula attenuates diabetic renal injuries by upregulating autophagy via inhibition of PLZF expression Zhao H, 2017 Diabetic (db/db) mice and high-glucose-induced NRK-52E cells Tangshen Formula Up-regulated the mitochondrial autophagy and down-regulated the collagen III protein Attenuated diabetic renal injuries by inhibiting urinary excretion of albumin and renal histological injuries doi: 10.1371/journal. pone.0171475. A/I, ablation and infarction; Cr, creatinine; TCM, traditional Chinese medicine; HIF-1α, Hypoxia-inducible factor 1-alpha; RIF, renal interstitial fibrosis; HG, high glucose; FAO, fatty acid oxidation; DN, diabetic nephropathy; CKD, chronic kidney disease; α-SMA, α-smooth muscle actin; PPARα, peroxisome proliferator-activated receptor alpha; Scr, serum creatinine; BUN, blood urea nitrogen; NT-proBNP, N-terminal pro-B-type natriuretic peptide; HK-2, human kidney-2 (human proximal tubular epithelial cell line); NRK-52E, normal rat kidney-52E (rat kidney tubular epithelial cell line); HEK293T, human embryonic kidney 293 T (antigen-T-transformed human embryonic kidney cell line). Scr, reduced serum creatinine; BUN, blood urea nitrogen; NT-proBNP, N-terminal pro-B-type natriuretic peptide. In conclusion, hypoxia-induced metabolic reprogramming plays a significant pathological role in the progression of DKD. Fortunately, TCM provides a panoramic therapeutic strategy for DKD by improving hypoxia, reversing metabolism, and enhancing mitochondrial function. Thus, targeting hypoxia-induced metabolic reprogramming represents a critical concept-driven therapeutic strategy for the management of DKD patients, which is worthy of further study.
Authors: Li Jiang, Xueming Zhang, Xiai Wu
Institutions: China-Japan Friendship Hospital, Karolinska Institutet
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4414451293