PMID- 34955823
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240404
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 12
DP  - 2021
TI  - Dual sEH/COX-2 Inhibition Using PTUPB-A Promising Approach to 
      Antiangiogenesis-Induced Nephrotoxicity.
PG  - 744776
LID - 10.3389/fphar.2021.744776 [doi]
LID - 744776
AB  - Kidney injury from antiangiogenic chemotherapy is a significant clinical 
      challenge, and we currently lack the ability to effectively treat it with 
      pharmacological agents. Thus, we set out to investigate whether simultaneous 
      soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a 
      dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating 
      antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, 
      sorafenib, which is known to cause serious renal side effects. The drug was 
      administered to male Sprague-Dawley rats that were on a high-salt diet. Sorafenib 
      was administered over the course of 56 days. The study included three 
      experimental groups; 1) control group (naive rats), 2) sorafenib group [rats 
      treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group 
      (rats treated with sorafenib only for the initial 28 days and subsequently 
      coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure 
      was measured every 2 weeks. After 28 days, sorafenib-treated rats developed 
      hypertension (161 +/- 4 mmHg). Over the remainder of the study, sorafenib treatment 
      resulted in a further elevation in blood pressure through day 56 (200 +/- 7 mmHg). 
      PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by 
      day 56, blood pressure was 159 +/- 4 mmHg. Urine was collected every 2 weeks for 
      biochemical analysis. After 28 days, sorafenib rats developed pronounced 
      proteinuria (9.7 +/- 0.2 P/C), which intensified significantly (35.8 +/- 3.5 P/C) by 
      the end of day 56 compared with control (2.6 +/- 0.4 P/C). PTUPB mitigated 
      sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. 
      Plasma and kidney tissues were collected on day 56. Kidney histopathology 
      revealed intratubular cast formation, interstitial fibrosis, glomerular injury, 
      and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment 
      reduced histological features by 30%-70% compared with the sorafenib-treated 
      group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on 
      the glomerular permeability barrier by decreasing angiotensin-II-induced 
      glomerular permeability to albumin. Finally, PTUPB improved in vitro the 
      viability of human mesangial cells. Collectively, our data demonstrate the 
      potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy 
      against sorafenib-induced glomerular nephrotoxicity.
CI  - Copyright (c) 2021 Jankiewicz, Barnett, Stavniichuk, Hwang, Hammock, Belayet, Khan 
      and Imig.
FAU - Jankiewicz, Wojciech K
AU  - Jankiewicz WK
AD  - Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, 
      Milwaukee, WI, United States.
FAU - Barnett, Scott D
AU  - Barnett SD
AD  - Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, 
      Milwaukee, WI, United States.
FAU - Stavniichuk, Anna
AU  - Stavniichuk A
AD  - Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, 
      Milwaukee, WI, United States.
FAU - Hwang, Sung Hee
AU  - Hwang SH
AD  - Department of Entomology and Nematology and Comprehensive Cancer Center, 
      University of California, Davis, Davis, CA, United States.
FAU - Hammock, Bruce D
AU  - Hammock BD
AD  - Department of Entomology and Nematology and Comprehensive Cancer Center, 
      University of California, Davis, Davis, CA, United States.
FAU - Belayet, Jawad B
AU  - Belayet JB
AD  - Department of Chemistry and Biochemistry, University of Wisconsin Milwaukee, 
      Milwaukee, WI, United States.
FAU - Khan, A H
AU  - Khan AH
AD  - Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, 
      Milwaukee, WI, United States.
FAU - Imig, John D
AU  - Imig JD
AD  - Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, 
      Milwaukee, WI, United States.
LA  - eng
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - R35 ES030443/ES/NIEHS NIH HHS/United States
PT  - Journal Article
DEP - 20211209
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC8695932
OTO - NOTNLM
OT  - cyclooxygenase (COX)
OT  - eicosanoids
OT  - glomerular injury
OT  - kidney injury
OT  - multitarget drugs
OT  - nephrotoxicity
OT  - soluble epoxide hydrolase (sEH)
OT  - vascular endothelial growth factor
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/12/28 06:00
MHDA- 2021/12/28 06:01
PMCR- 2021/12/09
CRDT- 2021/12/27 06:23
PHST- 2021/07/20 00:00 [received]
PHST- 2021/10/21 00:00 [accepted]
PHST- 2021/12/27 06:23 [entrez]
PHST- 2021/12/28 06:00 [pubmed]
PHST- 2021/12/28 06:01 [medline]
PHST- 2021/12/09 00:00 [pmc-release]
AID - 744776 [pii]
AID - 10.3389/fphar.2021.744776 [doi]
PST - epublish
SO  - Front Pharmacol. 2021 Dec 9;12:744776. doi: 10.3389/fphar.2021.744776. 
      eCollection 2021.