Cited by 202Chronic Kidney Disease and DiabetesAcute Kidney Injury ResearchDiabetes Treatment and Management

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The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?

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Hesp, Anne C., Schaub, Jennifer A., Prasad, Pottumarthi V., Vallon, Volker, Laverman, Gozewijn D., Bjornstad, Petter, van Raalte, Daniël H.·2020·Kidney International

DOI 10.1016/j.kint.2020.02.041PMC PMC8397597

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Abstract

Diabetic kidney disease is the most common cause of end-stage kidney disease and poses a major global health problem. Finding new, safe, and effective strategies to halt this disease has proven to be challenging. In part that is because the underlying mechanisms are complex and not fully understood. However, in recent years, evidence has accumulated suggesting that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and chronic kidney disease of other etiologies and was called the chronic hypoxia hypothesis. Hypoxia is the result of a mismatch between oxygen delivery and oxygen demand. The primary determinant of oxygen delivery is renal perfusion (blood flow per tissue mass), whereas the main driver of oxygen demand is active sodium reabsorption. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbate oxygen demand owing to increased sodium reabsorption as a result of sodium-glucose cotransporter upregulation and glomerular hyperfiltration. The resultant hypoxic injury creates a vicious cycle of capillary damage, inflammation, deposition of the extracellular matrix, and, ultimately, fibrosis and nephron loss. This review will frame the role of chronic hypoxia in the pathogenesis of diabetic kidney disease and its prospect as a promising therapeutic target. We will outline the cellular mechanisms of hypoxia and evidence for renal hypoxia in animal and human studies. In addition, we will highlight the promise of newer imaging modalities including blood oxygenation level-dependent magnetic resonance imaging and discuss salutary interventions such as sodium-glucose cotransporter 2 inhibition that (may) protect the kidney through amelioration of renal hypoxia.

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Background
Quantification of Renal Metabolic Rate of Oxygen
Deshpande, R. S., Langham, M. C., & Wehrli, F. W. (2023) · Springer eBooks · doi:10.1007/978-3-031-40169-5_30
Time to completely eradicate diabetic nephropathy
Din, U. A. S. E., Salem, M. M., & Abdulazim, D. O. (2023) · Diabetic Nephropathy · doi:10.1515/dine-2023-0005
Additional file 2 of SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease
Lu, Y.-P., Zhang, Z., Wu, H., Fang, L.-J., Hu, B., Tang, C., Zhang, Y., Yin, L., Tang, D., Zheng, Z., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21117692
Use of Transcriptome Sequencing to Analyze the Effects of Different Doses of an Astragalus-Rhubarb-Saffron Mixture in Mice with Diabetic Kidney Disease
Zhou, X., He, K., Zhao, J., et al. (2024) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s449792
Enfermedad renal diabética y polimorfismos de los genes ELMO1 y AGTR1: revisión sistemática
Martínez-Nava, Y., Ogaz-Escarpita, M. C., Reza‐López, S. A., et al. (2024) · Nefrología · doi:10.1016/j.nefro.2024.10.001
Transcriptomic-Based Identification of FCRL6 as a Novel Diagnostic Biomarker in Diabetic NephropathyPreprint
Marinedrive, A., Ray, S., & Mazumder, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.01.621451
“The hardening, thickening, and tightening of endothelial walls means patients with DM are at significantly higher risk of developing macrovascular complications due to a sustained limitation of oxygen flow (hypoxia) [ 3 ][ 4 ].”
Background
Hypertension in People with Diabetic and Chronic Kidney Disease, Obesity, and Renin Secreting Tumors
Khan, S. H., & Weir, M. R. (2025) · Updates in hypertension and cardiovascular protection · doi:10.1007/978-3-031-81292-7_3 · Cited by 1
Diagnostic Approaches in Hypertension and Chronic Kidney Disease Renal Markers in Evaluation and Follow-Up of Hypertension and Classical and Modern Imaging Techniques in Evaluation of BP Disorders
Burnier, M., Rodriguez, W. B., & Pruijm, M. T. (2025) · Updates in hypertension and cardiovascular protection · doi:10.1007/978-3-031-81292-7_13
Research Related to Respiratory Failure
游, 勇. (2025) · Advances in Clinical Medicine · doi:10.12677/acm.2025.1541150
The role of radiological imaging in the diagnosis of bilateral renal cortical necrosis: Case report and literature review
Mohammed, B., Jabrane, M., Mouad, E. O., et al. (2025) · Radiology Case Reports · doi:10.1016/j.radcr.2025.04.104
“Although the renal cortex receives 20%-25% of the cardiac output, while the medulla receives only about 10% of the blood flow from the cortex, the 2 regions are regulated by different mechanisms of blood flow [ 4 ].”
Magnetic Resonance Cartography of Renal Tubule Volume Fraction During Diuretic Intervention
Tasbihi, E., Gladytz, T., Millward, J. M., et al. (2025) · Acta Physiologica · doi:10.1111/apha.70095
Metabolic shifts in plasma amino acids and related metabolites in response to SGLT2 inhibition and hyperglycemia in type 1 diabetes
Kugathasan, L., Ragi, N., Debnath, S., Sridhar, V. S., Maity, S., Feng, T., Treviño, E., Perkins, B. A., Cherney, D. Z. I., & Sharma, K. (2025) · Physiological Reports · doi:10.14814/phy2.70465 · Cited by 3
Renal Metabolic Rate of Oxygen in Response to Hypoxia Challenges by Means of Quantitative MRI in Humans
Kamona, N., Hosseini, M., Langham, M. C., & Wehrli, F. W. (2025) · NMR in Biomedicine · doi:10.1002/nbm.70178
Liquid–Liquid Phase Separation-Related STAT1 Modulating Ubiquitination Aggravates the Progression of Diabetic Nephropathy via Promoting Inflammatory Response
Xue, S., Si, Y., & Han, X. (2025) · Journal of Interferon & Cytokine Research · doi:10.1177/10799907251396047
“It ’ s reported that chronic hypoxia may be the main patho-physiological pathway leading to DN (Hesp et al., 2020).”
Additional file 1 of SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease
Lu, Y., Zhang, Z., Wu, H.-W., Fang, L.-J., Hu, B., Tang, C., Zhang, Y., Yin, L., Tang, D.-E., Zheng, Z.-H., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21117686
SGL-TX-MR—study protocol acute effects of SGLT2 inhibitor on kidney allograft oxygen tension, a randomized, double-blind, placebo controlled crossover trial
Lange, L. B., & Bistrup, C. (2025) · Trials · doi:10.1186/s13063-025-09244-4
“The experiment has never been done on non-diabetic kidney transplant recipients, therefore, we rely on data found by Laursen et al. [31], who conducted this study on Danish type 1 diabetic patients.”
Effect of empagliflozin on urinary albumin excretion and hypoxic biomarkers in early diabetic kidney disease: A randomised double‐blind, placebo‐controlled trial
Makino, H., Kasahara, M., Takashima, R., et al. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70485
Type 1 Diabetes: Pathophysiology and Treatment Considerations for Cardiovascular Risk and Disease
Tommerdahl, K. L., & Bjornstad, P. (2026) · Elsevier eBooks · doi:10.1016/b978-0-323-87862-3.00005-7
Self-citation
Clinical utility of BOLD-MRI in accurate diagnosis and prognostic evaluation of diabetic nephropathy: a prospective renal biopsy-based cohort study
Wang, Q., Zhou, S., Niu, Y., Li, C., Lyu, Q., Chen, P., Zhang, X., Xie, L., Shen, W., Wang, Y., et al. (2026) · Insights into Imaging · doi:10.1186/s13244-026-02274-9 · Cited by 1
“BOLD-MRI can indirectly assess tissue oxygenation by detecting magnetic ﬁ eld disturbances caused by paramagnetic deoxyhemoglobin [13], providing insights into renal hypoxia, a key driver of diabetic kidney disease (DKD) progression under the “ chronic hypoxia hypothesis ” [14].”
Hypoxia inducible factor network reflects kidney disease progression in diabetes and sodium-glucose co-transporters inhibition
Nair, V., Minakawa, A., Smith, C., Berthier, C. C., Hartman, J., Menon, R., Fermin, D., Otto, E. A., Gisch, D. L., Eadon, M. T., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02653-0 · Cited by 1
“2 Though physiology suggests that there may be chronic hypoxia in DKD, model systems demonstrate that the HIF response is impaired in diabetes.”
Self-citation
Pathophysiology and pathogenesis of diabetic kidney disease
Cooper, M. E., & Thomas, M. C. (2026) · Elsevier eBooks · doi:10.1016/b978-0-12-815389-5.00042-3
Diabetic kidney disease: Radiological assessment and clinical correlations
Silipigni, S., Gembillo, G., Cicero, L. L., Ferrara, S. A., Ricca, M. F., Spadaro, G., Soraci, L., & Bottari, A. (2026) · World Journal of Diabetes · doi:10.4239/wjd.v17.i5.118278
Blood oxygen saturation and its associations with autonomic and peripheral neuropathy in diabetes
Brødsgaard, R. B., Laursen, J. C., Mizrak, H. I., Kufaishi, H., Hecquet, S. K., BrockD, B., Rossing, P. R., & Hansen, C. S. (2026) · Diabetes & Metabolism · doi:10.1016/j.diabet.2026.101773 · Cited by 1
Wnt5b/FZD1/LRP6 signaling drives renal fibrosis by triggering cytoplasmic stabilization and nuclear translocation of β-catenin under hypoxia
Wu, Z., Kuang, Z., Liu, J., Dong, G., Liang, L., Ma, S., Zou, F., & Wang, G. (2026) · iScience · doi:10.1016/j.isci.2026.116129
Multimodal Magnetic Resonance Imaging in Diabetic Kidney Disease: From Pathophysiological Insights to Clinical Applications
Ni, M., & Bingcang, H. (2026) · Diagnostics · doi:10.3390/diagnostics16111676
“Reduced sodium chloride delivery to the macula densa further stimulates glomerular filtration, creating a maladaptive feedback loop that ag-gravates hyperfiltration [52–54].”
Influential
Multi‐Parametric Magnetic Resonance Imaging to Assess Empagliflozin Effect on the Kidneys in People With Type 2 Diabetes Mellitus: A Pilot Clinical Trial
Lim, R. P., Qassin, S., McKenna, L., et al. (2026) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70950
Impact of the longitudinal evolution of impaired fasting glucose on cardio-kidney-metabolic multimorbidity
Chen, G., Zheng, H., Wang, Y., et al. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1812122
Association between extracellular-to-total body water ratio and eGFR decline in diabetic kidney disease: a longitudinal cohort study
Miyamoto, S., Imaishi, N., Morita, M., Uchida, H., Yamazaki, Y., Osue, M., Hirota, Y., Okamoto, M., Nagai, S., Sada, K., et al. (2026) · Clinical and Experimental Nephrology · doi:10.1007/s10157-026-02905-x
Silymarin attenuates diabetic nephropathy in rats via modulation of the miRNA-223/NLRP3/caspase-1/GSDMD axis and inflammasome-related pyroptotic signaling
Aboismaiel, M. G., Amin, M. N., & Eissa, L. A. (2026) · Biology Direct · doi:10.1186/s13062-026-00857-6
Impact of diabetes mellitus and glucose level control on early sepsis-associated acute kidney injury: a multicenter retrospective observational study
Zhao, L., Cui, Q., Dong, S., Wang, H., Yang, F., Wang, Y., Shi, H., Shi, X., Cao, D., Chen, Z., et al. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1878791
Multiparametric MRI for Early Chronic Kidney Disease Detection: Insights Into Renal Microcirculation
Zha, T., Pan, L., Yang, Y., Du, Y., Chen, Y., Wen, Q., Chen, J., Jiang, Z., & Xing, W. (2026) · NMR in Biomedicine · doi:10.1002/nbm.70358
“Renal perfusion is the primary determinant of tissue oxygenation, and persistent hypoxia plays a central role in CKD progression [32].”
From FLOW to translational positioning in chronic kidney disease: mechanistic complementarity of SGLT2 inhibitors and GLP-1 receptor agonists
Tian, X., Ma, X., Song, E., Li, X., Fu, W., He, H., Gao, Z., & Gao, B. (2026) · Translational research · doi:10.1016/j.trsl.2026.07.008
Zinc, type 2 diabetes, diabetic kidney disease: focus on hypoxia
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“It leads to vasoconstriction of renal arterioles, which further impairs oxygen delivery within the renal tubular interstitium (136).”
The nephron as a diseased unit: tubular epithelial programs and the fibrotic niche in CKD
Zoccali, C., Pollock, C., Mallamaci, F., et al. (2026) · Kidney International · doi:10.1016/j.kint.2026.04.045
Pathogenetic link between postpartum hemorrhage and renal cortical necrosis
Kumar, A. (2026) · Journal of Experimental Nephrology · doi:10.46439/nephrology.6.021
Clinical Physiology of SGLT2 Inhibitors in Non-diabetic and Diabetic Individuals
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A hypoxia-derived seven-gene signature reflects immune remodeling in diabetic kidney disease: integrated transcriptomic analysis and experimental validation
Liu, W. J., Zhang, J., Guo, X., et al. (2026) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2026.113568
The potential benefit of sodium glucose cotransporter (SGLT)-2 inhibitors in liver cirrhosis: A mini review
Spaan, M., Meijnikman, A. S., van Raalte, D. H., & Drenth, J. P. H. (2026) · Therapeutic Advances in Gastroenterology · doi:10.1177/17562848261485144
Targeting renal lipotoxicity with natural products in chronic kidney disease: mechanisms, molecular targets, and translational prospects
Liu, Y., Wei, J., Bai, L., et al. (2026) · Phytomedicine · doi:10.1016/j.phymed.2026.158832

Authors: Hesp, A. C., Schaub, J. A., Prasad, P. V., Vallon, V., Laverman, G. D., Bjornstad, P., & van Raalte, D. H.
Affiliations: Amsterdam University Medical Centers (NL)
University of Michigan (US)
Endeavor Health (US)
University of California San Diego (US)
Ziekenhuis Groep Twente (NL)
University of Colorado Anschutz (US)
Corresponding author: Hesp, Anne C.
ORCID: Hesp, Anne C.
Schaub, Jennifer A.
Prasad, Pottumarthi V.
Vallon, Volker
Laverman, Gozewijn D.
Bjornstad, Petter
Venue: Kidney International
Publisher: Elsevier BV
Published: 2020-09
Volume: 98
Issue: 3
Pages: 579-589
ISSN: 0085-2538 (ISSN-L)
DOI: 10.1016/j.kint.2020.02.041
PMC: PMC8397597
OpenAlex: W3020088156
Cited by: 202
References: 120
Citations by year: 2026: 30 · 2025: 34 · 2024: 25 · 2023: 38 · 2022: 40 · 2021: 32 · 2020: 3
FWCI: 4.59
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1461 d)
Locations: Kidney International (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
PubMed Central (acceptedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK106557)
National Institutes of Health (R01DK112042, R01DK106102, R01HL142814, RF1AG061296)
Topics: Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: diabetic nephropathy, renal hypoxia, oxygen delivery, oxygen requirement, sodium-glucose cotransporter 2 inhibition, SGLT2 inhibitors, renal perfusion, glomerular hyperfiltration, sodium reabsorption, renal fibrosis, extracellular matrix deposition, BOLD MRI, renal protection, end-stage renal disease
MeSH terms: Sodium-Glucose Transporter 2 Inhibitors, Animals, Hypoxia, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Humans, Hyperglycemia, Hypoglycemic Agents, Kidney

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The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?

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