Abstract
Renal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which Rrm2b has critical functions as reported. The Rrm2b kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. Rrm2b is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, Rrm2b deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.
Highlights
Ribonucleotide reductase catalyzes the rate-limiting step in the de novo reduction of ribonucleoside diphosphates to deoxyribonucleotide triphosphates during DNA synthesis and repair in the nucleus and mitochondria
Our data showed that Ribonucleotide reductase M2B (Rrm2b) deletion resulted in enhanced expression of reactive oxygen species (ROS)-associated genes, such as transformation related protein 53 (Trp53) and apurinic/apyrimidinic endonuclease 1 (Apex1/Ref1) (Fig. 2a), and reduced the expression of antioxidants, such as catalase (Cat) and superoxide dismutase 1 (Sod1) (Fig. 2b), in Rrm2b kiKO kidneys relative to control Rrm2b F/F kidneys
We found induced expression of genes associated with cell proliferation, such as cadherin 1 (Cdh1) and proliferating cell nuclear antigen (Pcna) (Fig. 2e), in Rrm2b kiKO mice, and increased cell proliferation was confirmed with IHC staining for ki[67] (Fig. 2f)
Summary
Ribonucleotide reductase (an α2β2 tetramer composed of two non-identical subunits) catalyzes the rate-limiting step in the de novo reduction of ribonucleoside diphosphates to deoxyribonucleotide triphosphates (dNTPs) during DNA synthesis and repair in the nucleus and mitochondria. Rrm2b plays critical roles in DNA repair, mitochondrial DNA (mtDNA) synthesis, oxidative stress resistance, cell cycle regulation and metastasis suppression[3,4,5,6,7,8]. Rrm2b can resist oxidative stress by scavenging reactive oxygen species (ROS) and is involved in the control of mitochondria homeostasis, including structural integrity and functional capacity[6,10,11,12,13]. In Rrm2b knockout mouse embryonic fibroblasts (MEFs), dNTP pools were severely attenuated under oxidative stress conditions. Rrm2b deficiency causes severe mtDNA deletion in various tissues in mice[4]. Compromised DNA repair in the nucleus and mitochondria can result in profound DNA damage and affect mitochondrial homeostasis, which can subsequently increase oxidative stress and cellular damage. We propose that Rrm2b deletion damages mitochondrial integrity and impedes the mitochondrial functions, resulting in the disruption of the homeostasis of mitochondrial metabolisms
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