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.