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-κB activity, and pathway array analysis revealed upregulation of
mRNA for NF-κB-dependent targets comprising numerous inflammatory mediators, including SAA itself (fold change 17.0, P=0.006). Inhibition of NF-κB 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.