Gender differences control the susceptibility to ER stress-induced acute kidney injury.
Endoplasmic reticulum (ER) stress contributes to acute kidney injury induced by several causes. Kidney dysfunction was shown to be influenced by gender differences. In this study we observed differences in the severity of kidney injury between male and female mice in response to tunicamycin, an ER stress agent. Tunicamycin-treated male mice showed a severe decline in kidney function and extensive kidney damage of proximal tubules in the kidney outer cortex (S1 and S2 segments). Interestingly, female tunicamycin-treated mice did not show a decline in kidney function, and their kidneys showed damage localized primarily to proximal tubules in the inner cortex (S3 segment). Protein markers of ER stress, glucose-regulated protein, and X-box binding protein 1 were also more elevated in male mice. Similarly, the induction of apoptosis was higher in tunicamycin-treated male mice, as measured by the activation of Bax and caspase-3. Testosterone administered to female mice before tunicamycin resulted in a phenotype similar to male mice with a comparable decline in renal function, tissue morphology, and induction of ER stress markers. We conclude that kidneys of male mice are much more susceptible to ER stress-induced acute kidney injury than those of females. Moreover, this sexual dimorphism could provide an interesting model to study the relation between kidney function and injury to a specific nephron segment.
Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA. rhodeify@uams.edu
Rawad
R
Hodeify
Judit
J
Megyesi
Adel
A
Tarcsafalvi
Hossam I
HI
Mustafa
Nang San
NS
Hti Lar Seng
Peter M
PM
Price
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D000071701:Regulatory Factor X Transcription Factors; D012727:Sex Characteristics; D013739:Testosterone / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism; D014415:Tunicamycin; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; C018551:glucose-regulated proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D013739:Testosterone; C505409:Casp3 protein, mouse; D053148:Caspase 3