Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534
Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\27821631
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2017 ; 28
(4
): 1093-1105
Nephropedia Template TP
Ma L
; Chou JW
; Snipes JA
; Bharadwaj MS
; Craddock AL
; Cheng D
; Weckerle A
; Petrovic S
; Hicks PJ
; Hemal AK
; Hawkins GA
; Miller LD
; Molina AJ
; Langefeld CD
; Murea M
; Parks JS
; Freedman BI
J Am Soc Nephrol
2017[Apr]; 28
(4
): 1093-1105
PMID27821631
show ga
APOL1 G1 and G2 variants facilitate kidney disease in blacks. To elucidate the
pathways whereby these variants contribute to disease pathogenesis, we
established HEK293 cell lines stably expressing doxycycline-inducible (Tet-on)
reference APOL1 G0 or the G1 and G2 renal-risk variants, and used Illumina human
HT-12 v4 arrays and Affymetrix HTA 2.0 arrays to generate global gene expression
data with doxycycline induction. Significantly altered pathways identified
through bioinformatics analyses involved mitochondrial function; results from
immunoblotting, immunofluorescence, and functional assays validated these
findings. Overexpression of APOL1 by doxycycline induction in HEK293 Tet-on G1
and G2 cells led to impaired mitochondrial function, with markedly reduced
maximum respiration rate, reserve respiration capacity, and mitochondrial
membrane potential. Impaired mitochondrial function occurred before intracellular
potassium depletion or reduced cell viability occurred. Analysis of global gene
expression profiles in nondiseased primary proximal tubule cells from black
patients revealed that the nicotinate phosphoribosyltransferase gene, responsible
for NAD biosynthesis, was among the top downregulated transcripts in cells with
two APOL1 renal-risk variants compared with those without renal-risk variants;
nicotinate phosphoribosyltransferase also displayed gene expression patterns
linked to mitochondrial dysfunction in HEK293 Tet-on APOL1 cell pathway analyses.
These results suggest a pivotal role for mitochondrial dysfunction in
APOL1-associated kidney disease.
free
free
free
