Serum amyloid A and inflammation in diabetic kidney disease and podocytes.
Authors Anderberg RJ, Meek RL, Hudkins KL, Cooney SK, Alpers CE, Leboeuf RC, Tuttle KR
Submitted By Submitted Externally on 3/4/2015
Status Published
Journal Laboratory investigation; a journal of technical methods and pathology
Year 2015
Date Published 3/1/2015
Volume : Pages 95 : 250 - 262
PubMed Reference 25531567
Abstract Inflammatory pathways are central mechanisms in diabetic kidney disease (DKD).
Serum amyloid A (SAA) is increased by chronic inflammation, but SAA has not been
previously evaluated as a potential DKD mediator. The aims of this study were to
determine whether SAA is increased in human DKD and corresponding mouse models
and to assess effects of SAA on podocyte inflammatory responses. SAA was
increased in the plasma of people with DKD characterized by overt proteinuria
and inversely correlated with estimated glomerular filtration rate
(creatinine-based CKD-EPI). SAA was also elevated in plasma of diabetic mouse
models including type 1 diabetes (streptozotocin/C57BL/6) and type 2 diabetes
(BTBR-ob/ob). SAA mRNA (Nephromine) was increased in human DKD compared with
non-diabetic and/or glomerular disease controls (glomerular fold change 1.5,
P=0.017; tubulointerstitium fold change 1.4, P=0.021). The kidneys of both
diabetic mouse models also demonstrated increased SAA mRNA (quantitative
real-time PCR) expression compared with non-diabetic controls (type 1 diabetes
fold change 2.9; type 2 diabetes fold change 42.5, P=0.009; interaction by model
P=0.57). Humans with DKD and the diabetic mouse models exhibited extensive SAA
protein deposition in the glomeruli and tubulointerstitium in similar patterns
by immunohistochemistry. SAA localized within podocytes of diabetic mice.
Podocytes exposed to advanced glycation end products, metabolic mediators of
inflammation in diabetes, increased expression of SAA mRNA (fold change 15.3,
P=0.004) and protein (fold change 38.4, P=0.014). Podocytes exposed to exogenous
SAA increased NF-?B activity, and pathway array analysis revealed upregulation
of mRNA for NF-?B-dependent targets comprising numerous inflammatory mediators,
including SAA itself (fold change 17.0, P=0.006). Inhibition of NF-?B reduced
these pro-inflammatory responses. In conclusion, SAA is increased in the blood
and produced in the kidneys of people with DKD and corresponding diabetic mouse
models. Podocytes are likely to be key responder cells to SAA-induced
inflammation in the diabetic kidney. SAA is a compelling candidate for DKD
therapeutic and biomarker discovery.

Investigators with authorship
Charles AlpersUniversity of Washington