Abstract
Five-sixths nephrectomy (5/6Nx) model is widely used for studying the mechanisms involved in chronic kidney disease (CKD) progression, a kidney pathology that has increased dramatically in recent years. Mitochondrial impairment is a key mechanism that aggravates CKD progression; however, the information on mitochondrial bioenergetics and redox alterations along a time course in a 5/6Nx model is still limited and in some cases contradictory. Therefore, we performed for the first time a time-course study of mitochondrial alterations by high-resolution respirometry in the 5/6Nx model. Our results show a decrease in mitochondrial β-oxidation at early times, as well as a permanent impairment in adenosine triphosphate (ATP) production in CI-linked respiration, a permanent oxidative state in mitochondria and decoupling of these organelles. These pathological alterations are linked to the early decrease in complex I and ATP synthase activities and to the further decrease in complex III activity. Therefore, our results may suggest that mitochondrial bioenergetics impairment is an early event in renal damage, whose persistence in time aggravates CKD development in the 5/6Nx model.
Highlights
Chronic kidney disease (CKD) is characterized by the progressive loss of nephrons, glomerular filtration rate (GFR) reduction, and the increase in renal damage markers during at least 3 months, generating progressive deterioration of the kidney function [1]
In the 5/6Nx model it has been shown that renal mass reduction induces mitochondrial bioenergetics alterations in organs like the heart [14] and skeletal muscle [11], our knowledge of renal mitochondrial disorders and their participation in CKD progression is limited because there is no information about the mitochondrial bioenergetics and redox state alterations over a time-course [4], in addition to the fact that the data on bioenergetics measurements and mitochondrial oxygen consumption made by low-resolution oximetry are scarce and in some cases are contradictory [15,16,17]
We previously reported that 5/6Nx induced the increase in the renal damage markers blood urea nitrogen (BUN) and creatinine in plasma 24 h post-surgery [18]
Summary
Chronic kidney disease (CKD) is characterized by the progressive loss of nephrons, glomerular filtration rate (GFR) reduction, and the increase in renal damage markers during at least 3 months, generating progressive deterioration of the kidney function [1]. In the 5/6Nx model it has been shown that renal mass reduction induces mitochondrial bioenergetics alterations in organs like the heart [14] and skeletal muscle [11], our knowledge of renal mitochondrial disorders and their participation in CKD progression is limited because there is no information about the mitochondrial bioenergetics and redox state alterations over a time-course [4], in addition to the fact that the data on bioenergetics measurements and mitochondrial oxygen consumption made by low-resolution oximetry are scarce and in some cases are contradictory [15,16,17]. The study of mitochondrial alterations in this interval would be of interest to elucidate the mechanisms involved in mitochondrial dysfunction and their role in CKD development in this model
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