PMID- 32616846
OWN - NLM
STAT- MEDLINE
DCOM- 20211011
LR  - 20211011
IS  - 1348-4214 (Electronic)
IS  - 0916-9636 (Print)
IS  - 0916-9636 (Linking)
VI  - 43
IP  - 11
DP  - 2020 Nov
TI  - Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone 
      (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, 
      combined with an angiotensin II receptor blocker.
PG  - 1204-1213
LID - 10.1038/s41440-020-0495-0 [doi]
AB  - Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was 
      recently approved in Japan to treat hypertension. In phase II and III studies, 
      esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the 
      urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic 
      nephropathy. To evaluate a direct renoprotective effect by MR blockade 
      independent of an antihypertensive effect in the context of diabetic nephropathy, 
      esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), 
      or both were orally administered to KK-Ay mice, a type 2 diabetes model, once 
      daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as 
      podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 
      8-hydroxy-2'-deoxyguanosine (8-OHdG), were measured, along with systolic blood 
      pressure (SBP), fasting blood glucose, and serum K(+) levels. Prior to the 
      initiation of drug administration, KK-Ay mice showed higher blood glucose, 
      insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic 
      control, indicating the development of diabetic renal injury. Combined treatment 
      with esaxerenone and olmesartan significantly reduced the change in UACR from 
      baseline compared with the change associated with vehicle at week 8 (-1.750 vs. 
      0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from 
      baseline compared with the change associated with vehicle at week 8 (P < 0.002). 
      The combination treatment also reduced urinary excretion of podocalyxin and 
      MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K(+) 
      levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic 
      nephropathy in KK-Ay mice without affecting SBP, suggesting that the 
      renoprotective effects of esaxerenone could be exerted independently of its 
      antihypertensive effect.
FAU - Arai, Kiyoshi
AU  - Arai K
AD  - End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. 
      arai.kiyoshi.ch@daiichisankyo.co.jp.
AD  - Global Project Management Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan. 
      arai.kiyoshi.ch@daiichisankyo.co.jp.
FAU - Morikawa, Yuka
AU  - Morikawa Y
AD  - Rare Disease & LCM Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
AD  - Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, 
      Japan.
FAU - Ubukata, Naoko
AU  - Ubukata N
AD  - End-Organ Disease Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
AD  - Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, 
      Japan.
FAU - Sugimoto, Kotaro
AU  - Sugimoto K
AD  - Medical Science Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20200702
PL  - England
TA  - Hypertens Res
JT  - Hypertension research : official journal of the Japanese Society of Hypertension
JID - 9307690
RN  - 0 (Angiotensin II Type 1 Receptor Blockers)
RN  - 0 (Imidazoles)
RN  - 0 (Mineralocorticoid Receptor Antagonists)
RN  - 0 (Pyrroles)
RN  - 0 (Sulfones)
RN  - 0 (Tetrazoles)
RN  - 8W1IQP3U10 (olmesartan)
RN  - N62TGJ04A1 (esaxerenone)
SB  - IM
MH  - Albuminuria/drug therapy
MH  - Angiotensin II Type 1 Receptor Blockers/pharmacology/*therapeutic use
MH  - Animals
MH  - Blood Pressure/drug effects
MH  - Diabetes Mellitus, Type 2/complications
MH  - Diabetic Nephropathies/*drug therapy
MH  - Drug Evaluation, Preclinical
MH  - Drug Therapy, Combination
MH  - Imidazoles/pharmacology/*therapeutic use
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mineralocorticoid Receptor Antagonists/pharmacology/*therapeutic use
MH  - Pyrroles/pharmacology/*therapeutic use
MH  - Sulfones/pharmacology/*therapeutic use
MH  - Tetrazoles/pharmacology/*therapeutic use
PMC - PMC7685977
OTO - NOTNLM
OT  - Albuminuria
OT  - Angiotensin II receptor blocker
OT  - Diabetic nephropathy
OT  - Esaxerenone
OT  - Mineralocorticoid receptor blocker
COIS- All authors are employees of Daiichi Sankyo Co., Ltd., Tokyo, Japan.
EDAT- 2020/07/04 06:00
MHDA- 2021/10/12 06:00
PMCR- 2020/07/02
CRDT- 2020/07/04 06:00
PHST- 2020/01/09 00:00 [received]
PHST- 2020/05/22 00:00 [accepted]
PHST- 2020/05/19 00:00 [revised]
PHST- 2020/07/04 06:00 [pubmed]
PHST- 2021/10/12 06:00 [medline]
PHST- 2020/07/04 06:00 [entrez]
PHST- 2020/07/02 00:00 [pmc-release]
AID - 10.1038/s41440-020-0495-0 [pii]
AID - 495 [pii]
AID - 10.1038/s41440-020-0495-0 [doi]
PST - ppublish
SO  - Hypertens Res. 2020 Nov;43(11):1204-1213. doi: 10.1038/s41440-020-0495-0. Epub 
      2020 Jul 2.