Laboratory Investigation 2015-03-01

Serum amyloid A and inflammation in diabetic kidney disease and podocytes.

Robert J Anderberg, Rick L Meek, Kelly L Hudkins, Sheryl K Cooney, Charles E Alpers, Renee C Leboeuf, Katherine R Tuttle

Index: Lab. Invest. 95(3) , 250-62, (2015)

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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-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.