A cellular protection racket: How lysosomal Ca2+ fluxes prevent kidney injury

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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Megalin in acute kidney injury: foe and friend

AJP Renal Physiology ◽

10.1152/ajprenal.00378.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. F147-F154 ◽

Cited By ~ 20

Author(s):

Ravikiran Mahadevappa ◽

Rikke Nielsen ◽

Erik Ilsø Christensen ◽

Henrik Birn

Keyword(s):

Acute Kidney Injury ◽

Animal Models ◽

Proximal Tubule ◽

Essential Role ◽

Kidney Injury ◽

Current Evidence ◽

Renal Protection ◽

Tubule Cell ◽

Cellular Protection ◽

And Function

The kidney proximal tubule is a key target in many forms of acute kidney injury (AKI). The multiligand receptor megalin is responsible for the normal proximal tubule uptake of filtered molecules, including nephrotoxins, cytokines, and markers of AKI. By mediating the uptake of nephrotoxins, megalin plays an essential role in the development of some types of AKI. However, megalin also mediates the tubular uptake of molecules implicated in the protection against AKI, and changes in megalin expression have been demonstrated in AKI in animal models. Thus, modulation of megalin expression in response to AKI may be an important part of the tubule cell adaption to cellular protection and regeneration and should be further investigated as a potential target of intervention. This review explores current evidence linking megalin expression and function to the development, diagnosis, and progression of AKI as well as renal protection against AKI.

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Hsp90 Relieves Heat Stress-Induced Damage in Mouse Kidneys: Involvement of Antiapoptotic PKM2-AKT and Autophagic HIF-1α Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms21051646 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1646

Author(s):

Bixia Chen ◽

Bo Yang ◽

Jie Zhu ◽

Jiaxin Wu ◽

Junzhou Sha ◽

...

Keyword(s):

Heat Stress ◽

Nuclear Translocation ◽

Kidney Injury ◽

Underlying Mechanism ◽

High Rate ◽

Future Research ◽

Hsp70 Expression ◽

Stress Injury ◽

Cellular Protection ◽

Stress Damage

Heat stress can particularly affect the kidney because of its high rate of adenosine triphosphate consumption. Competition between apoptosis and autophagy-mediated survival always exists in damaged tissue. And Hsp90 can enhance cellular protection to resist heat stress. However, the relationship between Hsp90 and the above competition and its underlying mechanism in the kidney are unclear. The present study found that heat stress induced obvious histopathological and oxidative injury, which was connected with cellular apoptosis and autophagy in the kidney and was associated with the levels of Hsp90 expression or function. The data showed that during heat stress, Hsp90 activated the PKM2-Akt signaling pathway to exert antiapoptotic effects and induce Hsp70 expression regulated by HSF-1, stimulated autophagy-mediated survival through the HIF-1α-BNIP3/BNIP3L pathway, and finally protected the kidney from heat-stress injury. Moreover, the nuclear translocation of PKM2, (p-) Akt, HSF-1, and HIF-1α was enhanced by heat stress, but only intranuclear p-Akt and HSF-1 were specifically influenced by Hsp90, contributing to regulate the cellular ability of resisting heat-stress damage. Our study provided new insights regarding the molecular mechanism of Hsp90 in the kidney in response to heat-stress injury, possibly contributing to finding new targets for the pharmacological regulation of human or animal acute kidney injury from heat stress in future research.

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Mesenchymal Stem Cells in Sepsis and Associated Organ Dysfunction: A Promising Future or Blind Alley?

Stem Cells International ◽

10.1155/2017/7304121 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Jan Horák ◽

Lukáš Nalos ◽

Vendula Martínková ◽

Jan Beneš ◽

Milan Štengl ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Organ Dysfunction ◽

Current Knowledge ◽

Kidney Injury ◽

Blind Alley ◽

Cellular Protection ◽

Cell Based Therapy ◽

Substantial Progress ◽

Life Threatening

Sepsis, newly defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, is the most common cause of death in ICUs and one of the principal causes of death worldwide. Although substantial progress has been made in the understanding of fundamental mechanisms of sepsis, translation of these advances into clinically effective therapies has been disappointing. Given the extreme complexity of sepsis pathogenesis, the paradigm “one disease, one drug” is obviously flawed and combinations of multiple targets that involve early immunomodulation and cellular protection are needed. In this context, the immune-reprogramming properties of cell-based therapy using mesenchymal stem cells (MSC) represent an emerging therapeutic strategy in sepsis and associated organ dysfunction. This article provides an update of the current knowledge regarding MSC in preclinical models of sepsis and sepsis-induced acute kidney injury. Recommendations for further translational research in this field are discussed.

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