Progressive Reduction in Mitochondrial Mass Is Triggered by Alterations in Mitochondrial Biogenesis and Dynamics in Chronic Kidney Disease Induced by 5/6 Nephrectomy.

Rodrigo Prieto-Carrasco,Pedro Rojas-Morales,Laura Gabriela Sánchez-Lozada,Edilia Tapia,José Pedraza-Chaverri,Rogelio Hernández-Pando,Fernando E García-Arroyo,Omar Emiliano Aparicio-Trejo,Juan Carlos León-Contreras

doi:10.3390/biology10050349

Abstract

Simple SummaryIn this work, we show for the first time a time-course study of the changes in mitochondrial biogenesis and dynamics markers in remnant renal mass from day 2 to day 28 after 5/6 nephrectomy. The present work shows a progressive reduction in mitochondrial biogenesis triggered by reducing two principal regulators of mitochondrial protein expression, the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) and the peroxisome proliferator-activated receptor alfa (PPARα). Additionally, we found a slow and gradual change in mitochondrial dynamics from fusion to fission, favoring mitochondrial fragmentation at later stages after 5/6Nx. These changes involved in chronic kidney disease (CKD) development provide important advances in the molecular study of this disease that is a growing worldwide health problem.The five-sixth nephrectomy (5/6Nx) model is widely used to study the mechanisms involved in chronic kidney disease (CKD) progression. Mitochondrial impairment is a critical mechanism that favors CKD progression. However, until now, there are no temporal studies of the change in mitochondrial biogenesis and dynamics that allow determining the role of these processes in mitochondrial impairment and renal damage progression in the 5/6Nx model. In this work, we determined the changes in mitochondrial biogenesis and dynamics markers in remnant renal mass from days 2 to 28 after 5/6Nx. Our results show a progressive reduction in mitochondrial biogenesis triggered by reducing two principal regulators of mitochondrial protein expression, the peroxisome proliferator-activated receptor-gamma coactivator 1-alpha and the peroxisome proliferator-activated receptor alpha. Furthermore, the reduction in mitochondrial biogenesis proteins strongly correlates with the increase in renal damage markers. Additionally, we found a slow and gradual change in mitochondrial dynamics from fusion to fission, favoring mitochondrial fragmentation at later stages after 5/6Nx. Together, our results suggest that 5/6Nx induces the progressive reduction in mitochondrial mass over time via the decrease in mitochondrial biogenesis factors and a slow shift from mitochondrial fission to fusion; both mechanisms favor CKD progression in the remnant renal mass.

Highlights

Renal function highly depends upon mitochondrion homeostasis; this organelle is the principal source of adenosine triphosphate (ATP) production in the kidney and is involved in several cellular signaling processes [1,2,3]
To confirm the presence of renal damage, we evaluated the level of the proteins kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), two renal damage markers associated principally with tubular injury, as well as the fibrotic markers TGF-β1 and α-SMA
KIM-1 and NGAL proteins showed a progressive increase in remnant kidney over time in the 5/6Nx group compared to the control group (Figure 1A,B), confirming tubular impairment progression

Summary

Introduction

Renal function highly depends upon mitochondrion homeostasis; this organelle is the principal source of adenosine triphosphate (ATP) production in the kidney and is involved in several cellular signaling processes [1,2,3]. Five-sixth nephrectomy (5/6Nx) is an experimental model widely used to study the mechanisms involved in CKD progression because renal ablation triggers progressive deterioration that emulates clinical CKD [12,13] In this model, early after surgery (1 day), the adaptive changes in remnant mass such as hypermetabolic state, hemodynamic changes, and hypertrophy trigger the impairment of mitochondrial bioenergetics [5,13], characterized by a reduction in the oxidative phosphorylation capacity (OXPHOS) and mitochondrial uncoupling [14]. We previously demonstrated that the impairment of mitochondrial bioenergetics observed from day 1 persisted until day 28 [15] Such an effect favors the decrease in mitochondrial β-oxidation and ATP production, favoring permanent oxidative stress in the mitochondria, triggering CKD development in the 5/6Nx model [15]. Their participation in renal damage progression in this model is presently unclarified

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Conclusion