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Pharmacologic control of oxidative stress and inflammation determines whether diabetic glomerulosclerosis progresses or decreases: A pilot study in sclerosis-prone mice.

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Date

2018-09-05

Authors

Grosjean, Fabrizio
Yubero-Serrano, Elena M
Zheng, Feng
Esposito, Vittoria
Swamy, Shobha
Elliot, Sharon J
Cai, Weijing
Vlassara, Helen
Salem, Fadi
Striker, Gary E

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Public Library of Science
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Abstract

Diabetic kidney disease (DKD) is characterized by progressive glomerulosclerosis (GS). ROP mice have a sclerosis-prone phenotype. However, they develop severe, rapidly progressive GS when rendered diabetic. Since GS also develops in aged C57Bl6 mice, and can be reversed using bone marrow from young mice which have lower oxidative stress and inflammation (OS/Infl), we postulated that this might also apply to DKD. Therefore, this pilot study asked whether reducing OS/Infl in young adult sclerosis-prone (ROP) diabetic mice leads to resolution of existing GS in early DKD using safe, FDA-approved drugs.After 4 weeks of stable streptozotocin-induced hyperglycemia 8-12 week-old female mice were randomized and treated for 22 weeks as follows: 1) enalapril (EN) (n = 8); 2) pyridoxamine (PYR)+EN (n = 8); 3) pentosan polysulfate (PPS)+EN (n = 7) and 4) PPS+PYR+EN (n = 7). Controls were untreated (non-DB, n = 7) and hyperglycemic (DB, n = 8) littermates. PPS+PYR+EN reduced albuminuria and reversed GS in DB. Treatment effects: 1) Anti-OS/Infl defenses: a) PPS+PYR+EN increased the levels of SIRT1, Nrf2, estrogen receptor α (ERα) and advanced glycation endproduct-receptor1 (AGER1) levels; and b) PYR+EN increased ERα and AGER1 levels. 2) Pro-OS/Infl factors: a) PPS+PYR+EN reduced sTNFR1, b) all except EN reduced MCP1, c) RAGE was reduced by all treatments. In summary, PYR+PPS+EN modulated GS in sclerosis-prone hyperglycemic mice. PYR+PPS+EN also decreased albuminuria, OS/Infl and the sclerosis-prone phenotype. Thus, reducing OS/Infl may reverse GS in early diabetes in patients, and albuminuria may allow early detection of the sclerosis-prone phenotype.

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MeSH Terms

Albumins
Animals
Creatinine
Diabetic Nephropathies
Disease Progression
Disease Susceptibility
Female

DeCS Terms

Albúminas
Creatinina
Nefropatías diabéticas
Progresión de la enfermedad
Susceptibilidad a enfermedades

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Keywords

Gene Expression Regulation, Mice, Mice, Inbred C57BL, Oxidative Stress, Pilot Projects

Citation

Grosjean F, Yubero-Serrano EM, Zheng F, Esposito V, Swamy S, Elliot SJ, et al. Pharmacologic control of oxidative stress and inflammation determines whether diabetic glomerulosclerosis progresses or decreases: A pilot study in sclerosis-prone mice. PLoS One. 2018 Sep 25;13(9):e0204366