Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid

Temporal Alterations in Mitochondrial β-Oxidation and Oxidative Stress Aggravate Chronic Kidney Disease Development in 5/6 Nephrectomy Induced Renal Damage

“…However, no changes were found in the evaluated times in complex II (CII, Figure 5D) and complex IV (CIV, Figure 5F) activities with respect to the Sham group. This lack of change in CII and CIV was also reported in the AKI-to-CKD transition model induced by folic acid [10], and has been related to a higher abundance of cysteine residues in CI and CIII, making these complexes more susceptible to oxidative stress [10,[27][28][29]. Furthermore, our results are congruent with the reports by Lash et al [15], who observed a slight increase in S3 in CII-linked respiration on day 10 of nephrectomy.…”

“…In fact, as we show in Figure 8, our results show that both CI-CIII dysfunction and β-oxidation impairment would be the principal therapeutic molecular target in mitochondria, since their functional preservation would prevent subsequent mitochondrial alterations in the 5/6Nx model. Although the 5/6Nx model does not fully cover the broad spectrum of pathologies included in CKD, other CKD progression models, like that induced by folic acid [10], also show a reduction in OXPHOS capacity related to CI-CIII and β-oxidation impairment. Furthermore, in this model, the preservation at early times of complexes' activities by N-acetylcysteine prevents β-oxidation impairment and the subsequent AKI-to-CKD transition [10].…”

“…On the other hand, renal function highly depends on mitochondrial function, making mitochondrial pathologies a common factor in the development of various kidney diseases [8,9]. Moreover, recent works suggest that renal mitochondrial alterations participate in the progression of several types of CKD in non-diabetic and in diabetic contexts [4,[10][11][12][13]. We recently showed that in folic acid-induced renal damage, mitochondria suffer pathological alterations, especially in bioenergetics and fatty acids (FA) β-oxidation parameters, that change along the transition to CKD [10].…”

“…Moreover, recent works suggest that renal mitochondrial alterations participate in the progression of several types of CKD in non-diabetic and in diabetic contexts [4,[10][11][12][13]. We recently showed that in folic acid-induced renal damage, mitochondria suffer pathological alterations, especially in bioenergetics and fatty acids (FA) β-oxidation parameters, that change along the transition to CKD [10]. Although 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].…”

Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction

“…25,33,49,51,67 Although progression of fibrosis involves several signaling pathways, the current information on the UUO model seems to suggest that preserving mitochondrial and ER function, especially the processes related to FA β-oxidation, can prevent, or at least delay, the fibrotic processes and loss of renal function. 7,23,33,51,98,120,122,123 Therefore, the steps that follow must involve not only a deeper description of the mechanisms involved in mitochondrial alterations and their pathological crosstalk with the ER, but also the temporal analysis of them. This is with the aim of developing more targeted mitochondrial therapies for future use in the clinic to treat obstructive nephropathy in patients.…”