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Reduction of proteinuria through podocyte alkalinization
#MMPMID24817115
Altintas MM
; Moriwaki K
; Wei C
; Möller CC
; Flesche J
; Li J
; Yaddanapudi S
; Faridi MH
; Gödel M
; Huber TB
; Preston RA
; Jiang JX
; Kerjaschki D
; Sever S
; Reiser J
J Biol Chem
2014[Jun]; 289
(25
): 17454-67
PMID24817115
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Podocytes are highly differentiated cells and critical elements for the
filtration barrier of the kidney. Loss of their foot process (FP) architecture
(FP effacement) results in urinary protein loss. Here we show a novel role for
the neutral amino acid glutamine in structural and functional regulation of the
kidney filtration barrier. Metabolic flux analysis of cultured podocytes using
genetic, toxic, and immunologic injury models identified increased glutamine
utilization pathways. We show that glutamine uptake is increased in diseased
podocytes to couple nutrient support to increased demand during the disease state
of FP effacement. This feature can be utilized to transport increased amounts of
glutamine into damaged podocytes. The availability of glutamine determines the
regulation of podocyte intracellular pH (pHi). Podocyte alkalinization reduces
cytosolic cathepsin L protease activity and protects the podocyte cytoskeleton.
Podocyte glutamine supplementation reduces proteinuria in LPS-treated mice,
whereas acidification increases glomerular injury. In summary, our data provide a
metabolic opportunity to combat urinary protein loss through modulation of
podocyte amino acid utilization and pHi.
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