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Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

ABSTRACT: Diabetes and its renal complications are major medical challenges worldwide. There are no effective drugs currently available for treating diabetes and diabetic kidney disease (DKD), especially in type 1 diabetes (T1D). Evidence has suggested that niclosamide ethanolamine salt (NEN) could improve diabetic symptoms in mice of type 2 diabetes (T2D). However, its role in T1D and DKD has not been studied to date. Here we report that NEN could protect against diabetes in streptozotocin (STZ) induced T1D mice. It increased serum insulin levels, corrected the unbalanced ratio of ?-cells to ?-cells, and induced islet morphologic changes under diabetic conditions. In addition, NEN could impede the progression of DKD in T1D. Specifically, it reduced urinary albumin levels, NAG, NGAL and TGF-?1 excretion, ameliorated renal hypertrophy, alleviated podocyte dysfunction, and suppressed the renal cortical activation of mTOR/4E-BP1 signaling pathway. Moreover, it is hepatoprotective and does not exhibit heart toxicity. Therefore, these findings open up a completely novel therapy for diabetes and DKD.

SUBMITTER: Han P

PROVIDER: S-EPMC5934567 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

Han Pengxun P Shao Mumin M Guo Lan L Wang Wenjing W Song Gaofeng G Yu Xuewen X Zhang Chunlei C Ge Na N Yi Tiegang T Li Shunmin S Du Heng H Sun Huili H

American journal of translational research 20180415 4

Diabetes and its renal complications are major medical challenges worldwide. There are no effective drugs currently available for treating diabetes and diabetic kidney disease (DKD), especially in type 1 diabetes (T1D). Evidence has suggested that niclosamide ethanolamine salt (NEN) could improve diabetic symptoms in mice of type 2 diabetes (T2D). However, its role in T1D and DKD has not been studied to date. Here we report that NEN could protect against diabetes in streptozotocin (STZ) induced ...[more]

PMID: 29736201

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Project description:In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.

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Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

Publications

Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

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