TY - JOUR
T1 - Pharmacologic control of oxidative stress and inflammation determines whether diabetic glomerulosclerosis progresses or decreases
T2 - A pilot study in sclerosis-prone mice
AU - Grosjean, Fabrizio
AU - Yubero-Serrano, Elena M.
AU - Zheng, Feng
AU - Esposito, Vittoria
AU - Swamy, Shobha
AU - Elliot, Sharon J.
AU - Cai, Weijing
AU - Vlassara, Helen
AU - Salem, Fadi
AU - Striker, Gary E.
N1 - Publisher Copyright:
© 2018 Grosjean et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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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U2 - 10.1371/journal.pone.0204366
DO - 10.1371/journal.pone.0204366
M3 - Article
C2 - 30252878
AN - SCOPUS:85054008961
VL - 13
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 9
M1 - e0204366
ER -