Abstract
Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned. In this study, we investigated the phenotypic and functional response of human primary PTEC to oxidative stress, an established driver of kidney disease. Furthermore, we examined the functional contribution of the underlying histopathology of the cortical tissue used to generate our PTEC. We demonstrated that human primary PTEC from both histologically ‘normal’ and ‘diseased’ cortical tissue responded to H2O2-induced oxidative stress with significantly elevated mitochondrial superoxide levels, DNA damage, and significantly decreased proliferation. The functional response of ‘normal’ PTEC to oxidative stress mirrored the reported pathogenesis of human kidney disease, with significantly attenuated mitochondrial function and increased cell death. In contrast, ‘diseased’ PTEC were functionally resistant to oxidative stress, with maintenance of mitochondrial function and cell viability. This selective survival of ‘diseased’ PTEC under oxidizing conditions is reminiscent of the in vivo persistence of maladaptive PTEC following kidney injury. We are now exploring the impact that these differential PTEC responses have in the therapeutic targeting of oxidative stress pathways.
Highlights
Kidney disease is a major public health problem, affecting approximately 10% of populations in industrialized countries [1]
Kidney cortical tissue was obtained from the macroscopically-healthy portion of renal cell carcinoma (RCC) nephrectomies from a total of ten donors with preserved kidney function
We demonstrate for the first time that, in contrast to human primary Proximal tubular epithelial cells (PTEC) from histologically ‘normal’ tissue, PTEC from histologically ‘diseased’ tissue are more resistant to high-level oxidative stress, with a preservation of mitochondrial function and cell viability
Summary
Kidney disease is a major public health problem, affecting approximately 10% of populations in industrialized countries [1]. The global burden of kidney disease continues to rise, driven by population growth, ageing, and the increased prevalence of diabetes and hypertension [2]. The development of disease within the kidney is characterized on renal biopsy by microstructural patterns of pathology, including arteriosclerosis, glomerulosclerosis, and tubular atrophy/interstitial fibrosis [3]. ROS, including mitochondrial superoxide (O2−), are natural byproducts of aerobic metabolism, and have significant functional roles in intracellular signaling and homeostasis. An imbalance between the cellular production of ROS and the capacity of cells to neutralize them results in oxidative stress [7]. Oxidative stress drives mitochondrial dysfunction associated with mitochondrial swelling and the loss of mitochondrial membrane potential (MMP), leading to altered gene expression and cell death via apoptotic or necrotic pathways [5]
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