Loss of Renal Tubular PGC-1α Exacerbates Diet-Induced Renal Steatosis and Age-Related Urinary Sodium Excretion in Mice

Svensson, Kristoffer; Schnyder, Svenia; Cardel, Bettina; Handschin, Christoph

doi:10.1371/journal.pone.0158716

Cited by 22 publications

(24 citation statements)

References 42 publications

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“…Mitochondrial biogenesis is regulated by a range of transcriptional co-activators and co-repressors 56,57 . One study has shown that PGC1α is a prominent regulator, at the transcriptional level, of oxidative phosphorylation, the TCA cycle and fatty acid metabolism in the kidney 58 . In that study, the investigators performed gene expression profiling of kidneys from control mice and nephron-specific inducible PPARGC1A -knockout (NiPKO) mice that had been fed a chow diet or high-fat diet (HFD).…”

Section: Maintaining Mitochondrial Homeostasismentioning

confidence: 99%

Mitochondrial energetics in the kidney

2017

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The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

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Section: Maintaining Mitochondrial Homeostasismentioning

confidence: 99%

Mitochondrial energetics in the kidney

2017

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“…While these studies strongly indicate a vital role of PGC-1α another group used an inducible nephron specific PGC-1α knockout mouse model to study the physiological role of PGC-1α in the kidney [ 86 ]. Results indicated the role of PGC-1α in mitochondrial metabolic systems is observed in the kidney similar to the previously described roles of PGC-1α in other tissues.…”

Section: Pgc-1α In Kidney Disease and Developmentmentioning

confidence: 99%

“…Results indicated the role of PGC-1α in mitochondrial metabolic systems is observed in the kidney similar to the previously described roles of PGC-1α in other tissues. After inducing the knockout at 12 weeks, researchers noted abnormal sodium excretion, most likely due to the decreased protein expression of sodium transporters NCCT and NKCC2 [ 86 ]. These phenotypes ultimately led to mice presenting with renal steatosis, although the authors hypothesize PGC-1α is dispensable for renal physiology due to mild phenotypes and high survival rates [ 86 ].…”

Section: Pgc-1α In Kidney Disease and Developmentmentioning

confidence: 99%

PGC-1α in Disease: Recent Renal Insights into a Versatile Metabolic Regulator

Chambers

Wingert

2020

Cells

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Peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) is perhaps best known as a master regulator of mitochondrial biogenesis and function. However, by virtue of its interactions as a coactivator for numerous nuclear receptors and transcription factors, PGC-1α also regulates many tissue-specific tasks that include adipogenesis, angiogenesis, gluconeogenesis, heme biosynthesis, thermogenesis, and cellular protection against degeneration. Knowledge about these functions continue to be discovered with ongoing research. Unsurprisingly, alterations in PGC-1α expression lead to a range of deleterious outcomes. In this review, we provide a brief background on the PGC-1 family with an overview of PGC-1α’s roles as an adaptive link to meet cellular needs and its pathological consequences in several organ contexts. Among the latter, kidney health is especially reliant on PGC-1α. Thus, we discuss here at length how changes in PGC-1α function impact the states of renal cancer, acute kidney injury (AKI) and chronic kidney disease (CKD), as well as emerging data that illuminate pivotal roles for PGC-1α during renal development. We survey a new intriguing association of PGC-1α function with ciliogenesis and polycystic kidney disease (PKD), where recent animal studies revealed that embryonic renal cyst formation can occur in the context of PGC-1α deficiency. Finally, we explore future prospects for PGC-1α research and therapeutic implications for this multifaceted coactivator.

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“…NiPKO mice exhibit a mild loss of sodium in urine, which is exacerbated in aged and HFD‐fed mice, suggesting the beneficial role of tubular PGC‐1α in sodium homeostasis under basal conditions, aging, and metabolic stress. In addition, NiPKO mice develop exacerbated kidney steatosis on a HFD (Svensson, Schnyder, Cardel, & Handschin, ).…”

Section: Role Of Pgc‐1α In Agingmentioning

confidence: 99%

PGC‐1α, a potential therapeutic target against kidney aging

et al. 2019

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Aging is defined as changes in an organism over time. The proportion of the aged population is markedly increasing worldwide. The kidney, as an essential organ with a high energy requirement, is one of the most susceptible organs to aging. It is involved in glucose metabolism via gluconeogenesis, glucose filtration and reabsorption, and glucose utilization. Proximal tubular epithelial cells (PTECs) depend on lipid metabolism to meet the high demand for ATP. Recent studies have shown that aging‐related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose and lipid metabolism. PGC‐1α is abundant in tissues, including kidney PTECs, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC‐1α by genetic or pharmacological intervention prevents telomere shortening and aging‐related changes in the skeletal muscle, heart, and brain. The activation of PGC‐1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC‐1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

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Loss of Renal Tubular PGC-1α Exacerbates Diet-Induced Renal Steatosis and Age-Related Urinary Sodium Excretion in Mice

Cited by 22 publications

References 42 publications

Mitochondrial energetics in the kidney

Mitochondrial energetics in the kidney

PGC-1α in Disease: Recent Renal Insights into a Versatile Metabolic Regulator

PGC‐1α, a potential therapeutic target against kidney aging

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