Increased Kidney Metabolism as a Pathway to Kidney Tissue Hypoxia and Damage: Effects of Triiodothyronine and Dinitrophenol in Normoglycemic Rats

Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow. Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of oxygen in tubular cells. Relative hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal anemia hinders oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of anemia with erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of antioxidants. Recent studies have elucidated the mechanism of hypoxia-induced transcription, namely that prolyl hydroxylase regulates hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.

Chronic kidney disease (CKD) is characterized by irreversible pathological processes that result in the development of end-stage renal disease (ESRD). Accumulating evidence has emphasized the important role of chronic hypoxia in the tubulointerstitium in the final common pathway that leads to development of ESRD. The causes of chronic hypoxia in the tubulointerstitium are multifactorial and include mechanisms such as hemodynamic changes and disturbed oxygen metabolism of resident kidney cells. Epidemiological studies have revealed an association between CKD and systemically hypoxic conditions, such as chronic obstructive pulmonary disease and sleep apnea syndrome. In addition to tubulointerstitial hypoxia, glomerular hypoxia can occur and is a crucial factor in the development of glomerular disorders. Chemical compounds, polarographic sensors, and radiographical methods can be used to detect hypoxia. Therapeutic approaches that target chronic hypoxia in the kidney should be effective against a broad range of kidney diseases. Amelioration of hypoxia is one mechanism of inhibiting the renin-angiotensin system, the current gold standard of CKD therapy. Future therapeutic approaches include protection of the vascular endothelium and appropriate activation of hypoxia-inducible factor, a key transcription factor involved in adaptive responses against hypoxia.

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.