Highlights
- Aging kidneys lose microvessel density, called microvascular rarefaction, which contributes to kidney sclerosis and functional decline
- Researchers used a short-lived fish model to study kidney aging and test the diabetes drug dapagliflozin (aka Farxiga®) which inhibits the protein SGLT2
- SGLT2 inhibitor treatment preserved capillary density, reduced albumin leakage, restored mitochondrial gene programs, and improved endothelial cell signaling
- While lifespan was not extended, kidney vascular structure and function were significantly preserved
- Findings suggest SGLT2 inhibitors may have direct protective and metabolic anti-aging effects in the kidney
Microvascular rarefaction: a silent driver of kidney aging
As we age, our kidneys gradually lose functional filtering units (nephrons), accumulate fibrosis, and develop structural changes collectively known as nephrosclerosis. One of the drivers of this decline is microvascular rarefaction: the progressive loss of kidney glomerulus and tubule-associated capillaries.
Capillaries are not just passive plumbing. They deliver oxygen, maintain metabolic balance (homeostasis), and maintain crucial signaling networks between the various capillary cells. When these capillaries disappear, parts of the kidney tissue are starved of oxygen, mitochondrial function declines, inflammation rises (‘inflammaging’), and fibrosis accelerates, creating a self-reinforcing loop of organ deterioration.
In this study published in the journal Kidney International, researchers used the African turquoise killifish, a naturally short-lived species with human-like kidney aging, to model kideney capillary decline and test whether the diabetes drug dapagliflozin could preserve kidney structure and function. Dapagliflozin belongs to a class of drugs that inhibit the protein Sodium-Glucose Cotransporter-2 (SGLT2) in the kidney, and are widely used to treat diabetes. They work by preventing glucose reabsorption in the proximal tubule of the kidney.
SGLT2 inhibition tested as a kideny vascular-protective intervention
The researchers first characterized how kidneys age in killifish. They observed classic signs of damage (nephrosclerosis) observed is aging human kidneys: scarring and damage to the glomerulus (glomerulosclerosis), kidney tubule loss, fibrosis, hardening of the arteries, and most notably, a significant loss of kidney capillary density. Albumin protein leakage into urine increased with age, again mimicking aging human kidneys, indicating impaired glomerular barrier integrity. There were also gene expression changes signifying aging: higher inflammation, decreased mitochondrial function, reduced signaling between capillary cells.
The team then administered dapagliflozin through diet and assessed structural, functional outcomes, and gene expression changes.
The study found that SGLT2 inhibition prevented age-associated kidney decline:
- Preserved microvassel structure: total vessel volume, branching points, and vascular network complexity increased compared to age-matched controls
- Reduced albumin protein in urine (albuminuria): a clear sign of better kidney tubule function
- Restored endothelial signaling: VEGF, laminin, and adhesion molecule signaling networks were partly preserved
- Restoration of mitochondrial gene expression kidney blood vessel and tubules: a sign of improvement in metabolism and overall kidney health
- Reduced inflammatory gene signatures associated with aging
Interestingly, lifespan itself was not extended. The benefits were organ-specific rather than systemic longevity effects. But a few of the key hallmarks of aging in the kidney tissue were clearly improved: mitochondrial function, intercellular communication and inflammation.This points to a potential mechanism beyond just glucose lowering.
Safety and translational considerations
This is a preclinical vertebrate study, not a human clinical trial. However, SGLT2 inhibitors such as dapagliflozin are already FDA-approved and widely used for diabetes, heart failure, and chronic kidney disease.
Because SGLT2 inhibitors are already approved drugs, these findings suggest that part of their benefit in people may be from improved blood vessel and mitochondrial health, and not just blood sugar control.
Whether these improvements translate to elderly people without kidney disease remains to be seen.
Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 2011 Oct 18;7(12):684–696. https://doi.org/10.1038/nrneph.2011.149
Paulmann A., Cox M.D., et al. Sodium-glucose co-transporter 2 inhibition improves age-dependent kidney microvascular rarefaction. Kidney International (2026). https://doi.org/10.1016/j.kint.2025.12.011
Simes B.C., et al. Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: A Clinician’s Guide. https://doi.org/10.2147/DMSO.S212003