The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a
promising target for newer renoprotective agents including SGLT2 inhibitors?
Authors Hesp AC, Schaub JA, Prasad PV, Vallon V, Laverman GD, Bjornstad P, van Raalte DH
Submitted By Petter Bjornstad on 8/11/2020
Status Published
Journal Kidney international
Year 2020
Date Published 4/1/2020
Volume : Pages Not Specified : Not Specified
PubMed Reference 32739206
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.