Hall, A.; (2010) The role of mitochondria in the renal Fanconi syndrome. Doctoral thesis , UCL (University College London).

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Abstract

Clinically, the renal proximal tubule (PT) seems to be vulnerable to mitochondrial dysfunction (MD), which can affect normal transport processes (including reabsorption of low molecular weight proteins [LMWPs]), resulting in the renal Fanconi syndrome. I wanted to explore why the PT is vulnerable to MD, and how this leads to impaired LMWP transport: (1) Using the OK cell line, to model uptake of LMWPs in the PT, I found respiratory chain (RC) inhibitors had minimal effect on the uptake of fluorescent-labelled albumin, and also had a relatively small impact on [ATP], which was maintained largely by glycolysis. Uptake of albumin was inhibited to a much greater extent by blockade of glycolysis, implying an important role for ATP. The RC inhibitor rotenone had a profound toxic effect on the structure of OK cells, due to extramitochondrial inhibition of microtubule polymerisation. (2) Multi-photon imaging of live rat kidney slices showed that mitochondrial membrane potential was lower in the PT relative to distal tubule, and was better maintained in the latter following RC inhibition. The basal rate of ROS production (per cell) and glutathione levels were both higher in the PT, and RC substrates were in a more oxidised state in this segment. (3) Urinary screening of adult patients with either (a) mitochondrial cytopathy, or (b) HIV and taking anti-retroviral therapy (ART) toxic to mitochondria, revealed high rates of tubular proteinuria (including LMWPs) in both groups. Patients taking ART had higher excretion of tubular proteins than those who were treatment naïve. In conclusion, inhibition of ATP generation impaired protein uptake in a model of the PT, and this was mirrored by increased tubular proteinuria in patients with either genetic or toxic MD. Furthermore, differences in mitochondrial function were demonstrated along the rodent nephron, which may render the PT vulnerable to MD.

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