PMID- 34680110
OWN - NLM
STAT- MEDLINE
DCOM- 20220118
LR  - 20220118
IS  - 2218-273X (Electronic)
IS  - 2218-273X (Linking)
VI  - 11
IP  - 10
DP  - 2021 Oct 7
TI  - GYY4137 Regulates Extracellular Matrix Turnover in the Diabetic Kidney by 
      Modulating Retinoid X Receptor Signaling.
LID - 10.3390/biom11101477 [doi]
LID - 1477
AB  - Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) 
      leading to renal fibrosis. Dysregulation of retinoic acid metabolism involving 
      retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been shown to 
      play a crucial role in diabetic nephropathy (DN). Furthermore, RARs and 
      peroxisome proliferator-activated receptor gamma (PPARgamma) are known to control the 
      RXR-mediated transcriptional regulation of several target genes involved in DN. 
      Recently, RAR and RXR have been shown to upregulate plasminogen activator 
      inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal 
      fibrosis during DN. Interestingly, hydrogen sulfide (H(2)S) has been shown to 
      ameliorate adverse renal remodeling in DN. We investigated the role of RXR 
      signaling in the ECM turnover in diabetic kidney, and whether H(2)S can mitigate 
      ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. We used wild-type 
      (C57BL/6J), diabetic (C57BL/6-Ins2(Akita)/J) mice and mouse mesangial cells (MCs) 
      as experimental models. GYY4137 was used as a H(2)S donor. Results showed that in 
      diabetic kidney, the expression of PPARgamma was decreased, whereas upregulations of 
      RXRalpha, RXRbeta, and RARgamma1 expression were observed. The changes were associated with 
      elevated PAI-1, MMP-9 and MMP-13. In addition, the expressions of collagen IV, 
      fibronectin and laminin were increased, whereas elastin expression was decreased 
      in the diabetic kidney. Excessive collagen deposition was observed predominantly 
      in the peri-glomerular and glomerular regions of the diabetic kidney. 
      Immunohistochemical localization revealed elevated expression of fibronectin and 
      laminin in the glomeruli of the diabetic kidney. GYY4137 reversed the 
      pathological changes. Similar results were observed in in vitro experiments. In 
      conclusion, our data suggest that RXR signaling plays a significant role in ECM 
      turnover, and GYY4137 modulates PPAR/RAR-mediated RXR signaling to ameliorate 
      PAI-1-dependent adverse ECM turnover in DN.
FAU - Juin, Subir Kumar
AU  - Juin SK
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY 40202, USA.
FAU - Pushpakumar, Sathnur
AU  - Pushpakumar S
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY 40202, USA.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology, University of Louisville School of Medicine, 
      Louisville, KY 40202, USA.
LA  - eng
GR  - DK116591/NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211007
PL  - Switzerland
TA  - Biomolecules
JT  - Biomolecules
JID - 101596414
RN  - 0 (GYY 4137)
RN  - 0 (Morpholines)
RN  - 0 (Organothiophosphorus Compounds)
RN  - 0 (PPAR gamma)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Pparg protein, mouse)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 5688UTC01R (Tretinoin)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
SB  - IM
MH  - Animals
MH  - Diabetic Nephropathies/*drug therapy/genetics/pathology
MH  - Extracellular Matrix/drug effects
MH  - Fibrosis/drug therapy/genetics/pathology
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Hydrogen Sulfide/pharmacology
MH  - Kidney/drug effects/pathology
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Morpholines/pharmacology
MH  - Organothiophosphorus Compounds/pharmacology
MH  - PPAR gamma/*genetics
MH  - Plasminogen Activator Inhibitor 1/*genetics
MH  - Receptors, Retinoic Acid/antagonists & inhibitors/genetics
MH  - Retinoid X Receptors/antagonists & inhibitors/*genetics
MH  - Signal Transduction/drug effects
MH  - Tretinoin/metabolism
PMC - PMC8533431
OTO - NOTNLM
OT  - GYY4137
OT  - diabetic kidney
OT  - extracellular matrix
OT  - mesangial cells
OT  - plasminogen activator inhibitor-1
OT  - retinoic acid receptor
OT  - retinoid X receptor
COIS- The authors declare no conflict of interest.
EDAT- 2021/10/24 06:00
MHDA- 2022/01/19 06:00
PMCR- 2021/10/07
CRDT- 2021/10/23 01:03
PHST- 2021/06/25 00:00 [received]
PHST- 2021/09/21 00:00 [revised]
PHST- 2021/10/04 00:00 [accepted]
PHST- 2021/10/23 01:03 [entrez]
PHST- 2021/10/24 06:00 [pubmed]
PHST- 2022/01/19 06:00 [medline]
PHST- 2021/10/07 00:00 [pmc-release]
AID - biom11101477 [pii]
AID - biomolecules-11-01477 [pii]
AID - 10.3390/biom11101477 [doi]
PST - epublish
SO  - Biomolecules. 2021 Oct 7;11(10):1477. doi: 10.3390/biom11101477.