Diabetic microcirculatory disturbances and pathologic erythropoiesis are provoked by deposition of amyloid-forming amylin in red blood cells and capillaries

Nirmal Verma, Miao Liu, Han Ly, Analia Loria, Kenneth S. Campbell, Heather Bush, Philip A. Kern, Pedro A. Jose, Heinrich Taegtmeyer, Donald M. Bers, Sanda Despa, Larry B. Goldstein, Andrew J. Murray, Florin Despa

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications.

Original languageEnglish
Pages (from-to)143-155
Number of pages13
JournalKidney International
Volume97
Issue number1
DOIs
StatePublished - Jan 2020

Bibliographical note

Funding Information:
This research was supported by National Institutes of Health grants HL118474 (to FD), HL135000 (to SD), AG057290 (to FD), and AG053999 (to FD); American Heart Association grants 16GRNT310200 (to FD) and 18PRE33990154 (to HL); and Alzheimer’s Association grant VMF-15-363458 (to FD). The University of Kentucky Center for Clinical & Translational Science Biostatistics, Epidemiology and Research Design and Biospecimens Cores are funded by the Clinical and Translational Science Awards grant UL1 TR001998.

Funding Information:
This research was supported by National Institutes of Health grants HL118474 (to FD), HL135000 (to SD), AG057290 (to FD), and AG053999 (to FD); American Heart Association grants 16GRNT310200 (to FD) and 18PRE33990154 (to HL); and Alzheimer's Association grant VMF-15-363458 (to FD). The University of Kentucky Center for Clinical & Translational Science Biostatistics, Epidemiology and Research Design and Biospecimens Cores are funded by the Clinical and Translational Science Awards grant UL1 TR001998. NV, ML, and HL conducted the experiments; NV and ML contributed equally; AL analyzed the kidney function data; KSC contributed the RBC samples and clinical data stored in the Center for Clinical & Translational Science Biobank; ML, NV, HL, SD, and FD analyzed the data; HB provided advice on the statistical methods and interpretation of the statistical analyses; PAK, PAJ, HT, DMB, LBG, and SD provided advice on the interpretation of the data analyses; AJM designed and assisted with the interpretation of the hypoxia experiments; and FD conceived the study and wrote the manuscript with contributions from all authors.

Publisher Copyright:
© 2019 International Society of Nephrology

Keywords

  • amylin
  • erythropoiesis
  • hypoxia
  • microvascular disease
  • type-2 diabetes

ASJC Scopus subject areas

  • Nephrology

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