Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress

Abstract

Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. It has so far been difficult to determine the role of kidney hypoxia per se for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg/day/kg by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion and histology were determined and compared to vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose or markers of oxidative stress, but increased kidney oxygen consumption and reduced cortical and medullary concentrations of glucose and glycogen and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…We demonstrated that TR CTLs boosted by PD-L1 mAb carry activated mitochondria with higher ROS production, and found that administration of ROS generators as well as uncouplers has synergistic effects with PD-1 blockade on tumor-growth inhibition. The uncouplers' synergistic effect may be due to their ability to induce cellular ROS through hypoxia or feedback mitochondrial proliferation, as a ROS scavenger cancelled the synergistic effect of uncouplers and CTLs stimulated with uncouplers contained higher ROS (34,35). We found that the administration of the uncouplers alone did not show a direct impact on the growth or gene expression of tumor cells.…”

“…Although chemical uncouplers are known to decrease ROS production in isolated mitochondria (30,31), there are reports that the uncouplers rather increase mitochondrial ROS production in cells through hypoxia and HIF-1α activity (32)(33)(34). We thus tested the effect of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol (DNP), and compared with oligomycin (an ATP synthase inhibitor) as control.…”

“…(ii) Uncouplers and ROS generators further enhance mitochondrial mass, resulting in increased ROS, which probably activates AMPK and mTOR for unknown reasons (34).…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[261][262][263][264][265] Therefore, by inducing pro-inflammatory adhesion molecules and chemokines, hypoxia causes the accumulation of macrophages in the kidney that produce profibrotic cytokines such as transforming growth factor β and activate renal fibrobalsts. 100,101,253 Hypoxia also activates fibroblasts directly to increase extracellular matrix deposition by increasing production of collagen and tissue inhibitor of metalloproteinase I and decreasing expression of collagenase. 266 This activation of fibroblasts, along with the recruitment of inflammatory cells and the damage done to tubular epithelial cells, all lead to tubulointerstitial fibrosis.…”

“…Under these circumstances urinary protein excretion, inflammatory cell infiltration into the kidney, and renal epithelial-to-mesenchymal transition were all increased. 100,101 Consequently, there appears to be a direct link between hypoxia and the progression of CKD.…”