Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice

Yi Lin, Makoto Kuro-o, Zhongjie Sun

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL+/-mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL+/- mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.

Original languageEnglish (US)
Pages (from-to)3855-3863
Number of pages9
JournalEndocrinology
Volume154
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Experimental Diabetes Mellitus
Kidney
Sirolimus
Genes
Diabetic Nephropathies
Streptozocin
Renal Circulation
Chronic Renal Insufficiency
Phosphorylation
Kidney Glomerulus
S 6
Blood Urea Nitrogen
Type 1 Diabetes Mellitus
Hypertrophy
Chronic Kidney Failure
Albumins
Urine

ASJC Scopus subject areas

  • Endocrinology

Cite this

Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice. / Lin, Yi; Kuro-o, Makoto; Sun, Zhongjie.

In: Endocrinology, Vol. 154, No. 10, 01.10.2013, p. 3855-3863.

Research output: Contribution to journalArticle

Lin, Yi ; Kuro-o, Makoto ; Sun, Zhongjie. / Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice. In: Endocrinology. 2013 ; Vol. 154, No. 10. pp. 3855-3863.
@article{b35cbd9b5bc243a9aac78cb91487f865,
title = "Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice",
abstract = "Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL+/-mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL+/- mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.",
author = "Yi Lin and Makoto Kuro-o and Zhongjie Sun",
year = "2013",
month = "10",
day = "1",
doi = "10.1210/en.2013-1053",
language = "English (US)",
volume = "154",
pages = "3855--3863",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "10",

}

TY - JOUR

T1 - Genetic deficiency of anti-aging gene klotho exacerbates early nephropathy in STZ-induced diabetes in male mice

AU - Lin, Yi

AU - Kuro-o, Makoto

AU - Sun, Zhongjie

PY - 2013/10/1

Y1 - 2013/10/1

N2 - Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL+/-mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL+/- mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.

AB - Klotho is a recently discovered anti-aging gene and is primarily expressed in kidneys. In humans, the klotho level decreases with age whereas the prevalence of chronic kidney disease (CKD) increases with age. Diabetic nephropathy is the most common form of CKD, which leads to end-stage renal disease. A decrease in klotho has been found in kidneys of patients with diabetic nephropathy. The purpose of this study is to assess whether klotho gene deficiency affects early diabetic nephropathy in a mouse of model of type 1 diabetes induced by streptozotocin (STZ). Male KL+/-mutant and wild-type mice (6-8 weeks) were injected with multiple low doses of STZ. Renal functions and renal blood flow were assessed. Kidneys were collected for histological examination and molecular assays of TGFβ1 and mammalian targets of rapamycin (mTOR) signaling. Klotho deficiency in KL+/- mutant mice exacerbated STZ-induced increases in urine albumin, blood urea nitrogen, expansion of mesangial matrix in renal glomeruli, and kidney hypertrophy, suggesting a protective role of klotho in kidney function and structure. Klotho deficiency did not affect renal blood flow. Notably, klotho deficiency significantly increased phosphorylation of Smad2, indicating enhanced TGFβ1 signaling in kidneys. Klotho deficiency also increased phosphorylation of mTOR and S6 (a downstream effector of mTOR), indicating enhanced mTOR signaling in kidneys of early diabetic mice. Thus, klotho gene deficiency may make kidneys more susceptible to diabetic injury. Klotho gene deficiency exacerbated early diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys.

UR - http://www.scopus.com/inward/record.url?scp=84884694421&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884694421&partnerID=8YFLogxK

U2 - 10.1210/en.2013-1053

DO - 10.1210/en.2013-1053

M3 - Article

C2 - 23928372

AN - SCOPUS:84884694421

VL - 154

SP - 3855

EP - 3863

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 10

ER -