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The tubular hypothesis of nephron filtration and diabetic kidney disease
Open accessAbstract
Kidney size and glomerular filtration rate (GFR) often increase with the onset of diabetes, and elevated GFR is a risk factor for the development of diabetic kidney disease. Hyperfiltration mainly occurs in response to signals passed from the tubule to the glomerulus: high levels of glucose in the glomerular filtrate drive increased reabsorption of glucose and sodium by the sodium-glucose cotransporters SGLT2 and SGLT1 in the proximal tubule. Passive reabsorption of chloride and water also increases. The overall capacity for proximal reabsorption is augmented by growth of the proximal tubule, which (alongside sodium-glucose cotransport) further limits urinary glucose loss. Hyperreabsorption of sodium and chloride induces tubuloglomerular feedback from the macula densa to increase GFR. In addition, sodium-glucose cotransport by SGLT1 on macula densa cells triggers the production of nitric oxide, which also contributes to glomerular hyperfiltration. Although hyperfiltration restores sodium and chloride excretion it imposes added physical stress on the filtration barrier and increases the oxygen demand to drive reabsorption. Tubular growth is associated with the development of a senescence-like molecular signature that sets the stage for inflammation and fibrosis. SGLT2 inhibitors attenuate the proximal reabsorption of sodium and glucose, normalize tubuloglomerular feedback signals and mitigate hyperfiltration. This tubule-centred model of diabetic kidney physiology predicts the salutary effect of SGLT2 inhibitors on hard renal outcomes, as shown in large-scale clinical trials.
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“In a paracrine manner, adenosine constricts the afferent arteriole through the adenosine 1 receptor, thereby decreasing glomerular perfusion and hyperfiltration, a central mechanism for progressive glomerular injury (21,22).”
From SGLT2 inhibition for CKD and cardiovascular disease in type 2 diabetes: report of a scientific workshop sponsored by the National Kidney Foundation (2021) · cites this paper as [22]
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Metadata
- Authors
- Vallon, V., & Thomson, S. C.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Vallon, Volker
- Venue
- Nature Reviews Nephrology
- Published
- 2020-03-09
- Volume
- 16
- Issue
- 6
- Pages
- 317-336
- ISSN
- 1745-8323 (ISSN-L)
- 1759-5061
- 1759-507X
- PMC
- PMC7242158
- OpenAlex
- W3009930262
- Cited by
- 465
- References
- 211
- Citations by year
- 2026: 80 · 2025: 75 · 2024: 79 · 2023: 70 · 2022: 79 · 2021: 55 · 2020: 24
- FWCI
- 9.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Nephrology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1rf1ag061296-01a1)
- National Institute on Aging (RF1-AG061296)
- National Heart, Lung, and Blood Institute (R01HL142814)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079337, R01DK106102, R01DK112042)
- 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, glomerular hyperfiltration, tubuloglomerular feedback, SGLT2, SGLT1, proximal tubular reabsorption, macula densa, nitric oxide, renal fibrosis, SGLT2 inhibitors, glomerular filtration rate
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Chlorides, Diabetes Mellitus, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Fibrosis, Glomerular Filtration Rate, Glucose, Humans, Hypertrophy, Inflammation, Kidney Glomerulus, Kidney Tubules, Nephrons, Nitric Oxide, Sodium, Cellular Senescence, Sodium-Glucose Transporter 1, Sodium-Glucose Transporter 2, Glomerular Filtration Barrier, Renal Reabsorption
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