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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?
Open accessAbstract
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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“First, it may be due to impaired oxygen delivery resulting from microvascular damage. Second, increased oxygen consumption, caused by both glomerular hyperfiltration and inefficient energy generation due to impaired insulin sensitivity, may also contribute (38).”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [38]
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Up-Date on Diabetic Nephropathy
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Stăniguț, A. M., Pana, C., Enciu, M., Deacu, M., Cîmpineanu, B., & Tuta, L. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810413 · Cited by 38
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Sridhar, V. S., Yau, K., Benham, J. L., Campbell, D. J. T., & Cherney, D. Z. I. (2022) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2022.04.007 · Cited by 23
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Yi, T. W., Sridhar, V. S., Scott, J., Nardone, M., & Cherney, D. Z. I. (2026) · Nature Reviews Nephrology · doi:10.1038/s41581-025-01042-0 · Cited by 24
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“It remains to be determined how GLP-1 confers its kidney benefits, as the only GLP-1 receptor that has been identified has limited expression in the kidney (8).”
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“Indeed, this reabsorption is dependent on the electrochemical gradient of sodium established by the Na/K co-transporter, consuming adenosine triphosphate generated by oxidation [83].”
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“This releases more MPs and inflammatory mediators, resulting in a vicious cycle and exacerbating thrombosis and kidney injury (Hesp et al., 2020; Dadson et al., 2020).”
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Ischemic tubular injury: Oxygen-sensitive signals and metabolic reprogramming
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Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes
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“36, 50 MRI offers non-invasive non-invasive full coverage of the kidney, and the MRI relaxation times T 2 *, T 2 appear to”
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“Apart from the activation of the TGF, other mechanisms for the beneficial effects of SGLT2i on kidney function have been proposed (Table 1): induction of ketone body production and an elevation in hematocrit concentration, which can contribute to the beneficial effect of these agents on cardiovascular outcomes [30]; l…”
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“Adding an SGLT2i may decrease hypoxia-inducible factor-1alpha (HIF-1alpha) in the kidney, revealing less tissue hypoxia [57].”
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More reasons to use SGLT2 inhibitors: EMPEROR-reduced and DAPA-CKD
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Pathophysiology of Diabetic Kidney Disease
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Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside
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Metadata
- 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
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 98
- Issue
- 3
- Pages
- 579-589
- ISSN
- 0085-2538 (ISSN-L)
- 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
- 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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