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2017 ; 8
(44
): 75808-75821
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Albuminuria confers renal resistance to loop diuretics via the stimulation of
NLRP3 inflammasome/prostaglandin signaling in thick ascending limb
#MMPMID29100270
Zhuang Y
; Jia Z
; Hu C
; Ding G
; Zhang X
; Zhang Y
; Yang G
; Rohatgi R
; Huang S
; He JC
; Zhang A
Oncotarget
2017[Sep]; 8
(44
): 75808-75821
PMID29100270
show ga
Renal resistance to loop diuretics is a frequent complication in a number of
kidney disease patients with elusive mechanism. Employing human renal biopsy
specimens, albumin overload mouse model, and primary cultures of mouse renal
tubular cells, albuminuria effect on NKCC2 expression and function and the
underlying mechanisms were investigated. In the renal biopsy specimens of
albuminuric patients, we found that NKCC2 was significantly downregulated with a
negative correlation with albuminuria severity as examined by
immunohistochemistry. Meanwhile, NLRP3 and mPGES-1 were stimulated in NKCC2
positive tubules (thick ascending limb, TAL) paralleled with increased urinary
PGE2 excretion. To examine the role of albuminuria in the downregulation of NKCC2
and the potential role of NLRP3/prostaglandin signaling in NKCC2 downregulation,
an albumin overload mouse model was employed. Interestingly, we discovered that
albuminuria downregulated NKCC2 protein expression in murine kidney and impaired
the renal response to loop diuretic furosemide. Specifically, albuminuria
suppressed NKCC2 expression and function through NLRP3/prostaglandin dependent
signaling in TAL. In primary cultures of renal tubular cells, albumin directly
reduced NKCC2 but enhanced NLRP3, COX-2, and mPGES-1 expression. These novel
findings demonstrated that albuminuria is of importance in mediating the renal
resistance to loop diuretics via NLRP3/prostaglandin signaling-dependent NKCC2
downregulation in TAL. This may also offer novel, effective targets for dealing
with the resistance of loop diuretics in proteinuric renal diseases.