Abstract
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.
Highlights
Disordered salt and water handling is a common complication of many types of kidney disease
Kidney biopsy specimens from patients with primary glomerular disease who presented with obvious proteinuria without reaching the diagnostic standard of nephrotic syndrome were chosen for the analysis to avoid the influence of blood volume depletion cause by fluid redistribution
Employing an albumin-overload mouse model, we observed a significant increase of NOD-like receptor family (NLRP3) expression in renal tubules of WT mice contrasting to an absence of NLRP3 signaling in NLRP3−/− animals (Figure 3A)
Summary
Disordered salt and water handling is a common complication of many types of kidney disease. Though substantial progress has been made in understanding the physiologic role of kidneys in regulating salt and water balance, the www.impactjournals.com/oncotarget pathogenesis of the renal resistance to loop diuretics in NS remains elusive. The inflammasome is an intracellular multi-protein complex comprising caspase-1, PYCARD and NALP that initiates the innate immune response to a pathogen-associated and/or damageassociated molecular pattern. This process can cause cellular injury through inflammatory cytokines (IL-1β and IL-18) activated by caspase-1 [6,7,8]. Among the NLR family members (NLRP1, NLRP2, NLRP3, NLRP6, NLRP12, and NLRC4), NLRP3 deficient mice had less tubular injury, inflammation, and renal fibrosis in chronic kidney disease (CKD) [11]
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