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PLoS One. 2019 Feb 14;14(2):e0211555. doi: 10.1371/journal.pone.0211555. eCollection 2019.

Serum amyloid A and Janus kinase 2 in a mouse model of diabetic kidney disease.

Author information

1
Providence Medical Research Center, Providence Health Care, Spokane, Washington, United States of America.
2
Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
3
Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States of America.
4
Institute of Translational Health Sciences, Kidney Research Institute, Nephrology Division University of Washington, Seattle, Washington, United States of America.

Abstract

BACKGROUND:

Serum amyloid A (SAA), a potent inflammatory mediator, and Janus kinase 2 (JAK2), an intracellular signaling kinase, are increased by diabetes. The aims were to elucidate: 1) a JAK2-mediated pathway for increased SAA in the kidneys of diabetic mice; 2) a JAK2-SAA pathway for inflammation in podocytes.

METHODS:

Akita diabetic mice (129S6) with podocyte JAK2 overexpression and angiotensin II infusion (4 weeks) were given a JAK1,2 inhibitor (LY03103801, 3 mg/kg/day orally for the last two weeks). Kidneys were immunostained for SAA isoform 3 (SAA3). SAA3 knockout and control mouse podocytes were exposed to advanced glycation end products (AGE) or exogenous SAA with JAK2 inhibition (Tyrphostin AG 490, 50μM). JAK2 activity (phosphorylation, Western blot, 1 hour) and mRNA for SAA3 and associated inflammatory genes (Cxcl5, Ccl2, and Ccl5) were measured by RT-PCR (20 hours).

RESULTS:

SAA3 protein was present throughout the diabetic kidney, and podocyte JAK2 overexpression increased tubulointerstitial SAA3 compared to wild type diabetic controls, 43% versus 14% (p = 0.007); JAK1,2 inhibition attenuated the increase in SAA3 to 15% (p = 0.003). Urine albumin-to-creatinine ratio (r = 0.49, p = 0.03), mesangial index (r = 0.64, p = 0.001), and glomerulosclerosis score (r = 0.51, p = 0.02) were associated with SAA3 immunostaining scores across mouse groups. Exposing podocytes to AGE or exogenous SAA increased JAK2 activity within one hour and mRNA for associated inflammatory genes after 20 hours. JAK2 inhibition reduced SAA3 mRNA expression in podocytes exposed to AGE or SAA. SAA3 knockout podocytes had >85% lower AGE-induced inflammatory genes.

CONCLUSION:

JAK1,2 inhibition reduced SAA and histological features of DKD in podocyte JAK2-overexpressing mice. In podocytes exposed to a diabetes-like condition, JAK2 inhibition reduced expression of SAA, while SAA knockout blocked expression of associated pro-inflammatory mediators. SAA may promote JAK2-dependent inflammation in the diabetic kidney.

Conflict of interest statement

K.R.T. has received consulting support from Eli Lilly and Company, Boehringer-Ingelheim, Gilead and Astra Zeneca. F.C.B. III, through the University of Michigan, has received grant/research support from Eli Lilly and Company, Bristol-Myers Squibb and Takeda Pharmaceuticals. M.K., through the University of Michigan, has received grant/research support and/or consulting support from Eli Lilly and Company, Abbvie, Astra-Zeneca, Boehringer-Ingelheim, Novo-Nordisk and Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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