Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

Jessica R Mader; Zachary T Resch; Gary R McLean; Jakob Hauge Mikkelsen; Claus Oxvig; Ronald J Marler; Cheryl A. Conover

doi:10.1530/JOE-13-0167

Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

Jessica R Mader, Zachary T Resch, Gary R McLean, Jakob Hauge Mikkelsen, Claus Oxvig, Ronald J Marler, Cheryl A. Conover

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Abstract

We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

Original language	English
Journal	Journal of Endocrinology
Volume	219
Issue	1
Pages (from-to)	51-58
Number of pages	8
ISSN	0022-0795
DOIs	https://doi.org/10.1530/JOE-13-0167
Publication status	Published - 1 Oct 2013

Keywords

Aging
Animals
Bowman Capsule
Diabetes Mellitus, Experimental
Diabetic Nephropathies
Female
Glomerular Mesangium
Humans
Kidney
Kidney Glomerulus
Mice
Mice, Knockout
Pregnancy
Pregnancy-Associated Plasma Protein-A

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10.1530/JOE-13-0167

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title = "Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy",

abstract = "We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.",

keywords = "Aging, Animals, Bowman Capsule, Diabetes Mellitus, Experimental, Diabetic Nephropathies, Female, Glomerular Mesangium, Humans, Kidney, Kidney Glomerulus, Mice, Mice, Knockout, Pregnancy, Pregnancy-Associated Plasma Protein-A",

author = "Mader, {Jessica R} and Resch, {Zachary T} and McLean, {Gary R} and Mikkelsen, {Jakob Hauge} and Claus Oxvig and Marler, {Ronald J} and Conover, {Cheryl A.}",

year = "2013",

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doi = "10.1530/JOE-13-0167",

language = "English",

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journal = "Journal of Endocrinology",

issn = "0022-0795",

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TY - JOUR

T1 - Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

AU - Mader, Jessica R

AU - Resch, Zachary T

AU - McLean, Gary R

AU - Mikkelsen, Jakob Hauge

AU - Oxvig, Claus

AU - Marler, Ronald J

AU - Conover, Cheryl A.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

AB - We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

KW - Aging

KW - Animals

KW - Bowman Capsule

KW - Diabetes Mellitus, Experimental

KW - Diabetic Nephropathies

KW - Female

KW - Glomerular Mesangium

KW - Humans

KW - Kidney

KW - Kidney Glomerulus

KW - Mice

KW - Mice, Knockout

KW - Pregnancy

KW - Pregnancy-Associated Plasma Protein-A

U2 - 10.1530/JOE-13-0167

DO - 10.1530/JOE-13-0167

M3 - Journal article

C2 - 23881937

SN - 0022-0795

VL - 219

SP - 51

EP - 58

JO - Journal of Endocrinology

JF - Journal of Endocrinology

IS - 1

ER -

Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy

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