Mechanisms of Disease: the hypoxic tubular hypothesis of diabetic nephropathy

Traditionally thought of as a primarily glomerular disease, evidence is accumulating to support early involvement of tubular and interstitial dysfunction in the development of diabetic nephropathy. This Review focuses on the role of chronic hypoxia in the tubulointerstitium as a major factor in the pathogenesis of diabetic nephropathy, and touches on the status of potentially beneficial clinical interventions. Diabetic nephropathy is traditionally considered to be a primarily glomerular disease, although this contention has recently been challenged. Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact. Chronic hypoxia of the tubulointerstitium has been recognized as a mechanism of progression that is common to many renal diseases. The hypoxic milieu in early-stage diabetic nephropathy is aggravated by manifestations of chronic hyperglycemia—abnormalities of red blood cells, oxidative stress, sympathetic denervation of the kidney due to autonomic neuropathy, and diabetes-mellitus-induced tubular apoptosis; as such, tubulointerstitial hypoxia in diabetes mellitus might be an important early event. Chronic hypoxia could have a dominant pathogenic role in diabetic nephropathy, not only in promoting progression but also during initiation of the condition. Early loss of tubular and peritubular cells reduces production of 1,25-dihydroxyvitamin D3 and erythropoietin, which, together with dysfunction of their receptors caused by the diabetic state, diminishes the local trophic effects of the hormones. This diminution could further compromise the functional and structural integrity of the parenchyma and contribute to the gradual decline of renal function. Key Points Traditionally thought of as a primarily glomerular disease, evidence is accumulating to support early involvement of tubular and interstitial dysfunction in diabetic nephropathy Several features of diabetes mellitus (e.g. enhanced production of reactive oxygen species, low concentrations of 1,25-dihydroxyvitamin D3, structural lesions, hypertension, interstitial fibrosis, abnormal red blood cells, and anemia) contribute to the generation of hypoxic conditions in renal tubules Proteinuria might be a marker of tubulointerstitial injury in early diabetic renal disease Altered sodium handling in the proximal tubules of people with diabetes mellitus probably contributes to glomerular hyperfiltration, which in turn might lead to functional tubular hypoxi