Oxygen Metabolism in Experimental Kidney Disease

Abstract: Tubulointerstitial hypoxia has been proposed a unifying mechanism behind the development of chronic kidney disease (CKD), regardless of primary diagnosis. Important factors that contribute to the development of hypoxia are reduced bioavailability of nitric oxide (NO), oxidative stress and mitochondria uncoupling. Diabetes and hypertension are the leading causes of CKD. Once established, CKD is a progressive disease and there is no curative treatment. This thesis aimed to investigate the in vivo kidney oxygen metabolism and in vitro mitochondria function in animal models of pathological conditions known to cause kidney injury.The immunosuppressant drug rapamycin has been suggested to counteract diabetic nephropathy by reducing kidney hypertrophy and proteinuria. In a rat model of diabetes type 1, we demonstrate that rapamycin induced intrarenal hypoxia, oxidative stress and mitochondria leak respiration. In diabetic animals, these changes, together with diabetes induced tubular injury, were further aggravated by rapamycin. Proteinuria was decreased by rapamycin in diabetic animals, due to altered glomerular permeability of large molecules. When investigating the role of hypoxia in development of nephropathy there are often confounding factors such as concomitant hyperglycemia, hypertension and oxidative stress to consider. In rats, we demonstrate that increased kidney metabolism, induced by increased thyroid hormone signaling, induced kidney hypoxia, proteinuria and mitochondria leak respiration. Importantly blood glucose, blood pressure and oxidative stress was unchanged. This provides further evidence that hypoxia per se can induce kidney injury. The role of mitochondria dysfunction in hypertensive kidney disease is unclear and angiotensin II (Ang II) has been shown to inhibit mitochondria respiration. In a mouse model of hypertension, we demonstrate that Ang II regulation of mitochondria respiration was dose-dependent. Low Ang II signaling increased leak respiration without compromising efficiency of oxidative phosphorylation. In contrast, high Ang II signaling inhibited mitochondria respiration and decreased efficiency of oxidative phosphorylation. Finally, uremic toxins accumulate in patients with CKD and correlate with the degree of decline in kidney function. In a rat model of CKD, we demonstrate that treatment to reduce plasma levels of protein bound uremic toxins improves cardiac output and kidney oxygenation. In summary, the common denominator for pathological conditions investigated in this thesis is the occurrence of intrarenal hypoxia. This thesis demonstrates that increased mitochondria oxygen consumption via leak respiration as an important contributing factor. Further, targeting plasma levels of circulating uremic toxins may be a potential treatment strategy to slow the rate of progression of CKD.