scholarly journals Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
John E. Bylander ◽  
Faihaa Ahmed ◽  
Sabena M. Conley ◽  
Jean-Marie Mwiza ◽  
Elimelda Moige Ongeri
Keyword(s):  
Type 1 Diabetes ◽  
Survival Rates ◽  
Kidney Injury ◽  
Diabetic Kidney ◽  
Nitrogen Levels ◽  
Protein Levels ◽  
Urine Albumin ◽  
Membrane Bound

Meprins are membrane-bound and secreted metalloproteinases consisting of α and/or β subunits that are highly expressed in kidney epithelial cells and are differentially expressed in podocytes and leukocytes (macrophages and monocytes). Several studies have implicated meprins in the progression of diabetic nephropathy (DN) and fibrosis-associated kidney disease. However, the mechanisms by which meprins modulate DN are not understood. To delineate the role of meprins in DN, we subjected meprin αβ knockout (αβKO) mice and their wild-type (WT) counterparts to streptozotocin-induced type 1 diabetes. The 18-week survival rates were significantly lower for diabetic meprin αβKO mice when compared to those for their WT counterparts. There were significant decreases in mRNA and protein levels for both meprin α and β in diabetic WT kidneys. Furthermore, the blood urea nitrogen levels and urine albumin/creatinine ratios increased in diabetic meprin αβKO but not in diabetic WT mice, indicating that meprins may be protective against diabetic kidney injury. The brush border membrane levels of villin, a meprin target, significantly decreased in diabetic WT but not in diabetic meprin αβKO kidneys. In contrast, isoform-specific increases in cytosolic levels of the catalytic subunit of PKA, another meprin target, were demonstrated for both WT and meprin αβKO kidneys.

scholarly journals LC-MS-based metabolomics analysis to identify meprin-β-associated changes in kidney tissue from mice with STZ-induced type 1 diabetes and diabetic kidney injury

2019 ◽  
Vol 317 (4) ◽  
pp. F1034-F1046 ◽  
Author(s):  
Jessica Gooding ◽  
Lei Cao ◽  
Faihaa Ahmed ◽  
Jean-Marie Mwiza ◽  
Mizpha Fernander ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Liquid Chromatography ◽  
Kidney Injury ◽  
Variable Importance ◽  
Proteolytic Processing ◽  
Indoxyl Sulfate ◽  
Pima Indians ◽  
Diabetic Kidney ◽  
Metabolomics Analysis

Meprin metalloproteases have been implicated in the pathophysiology of diabetic kidney disease (DKD). Single-nucleotide polymorphisms in the meprin-β gene have been associated with DKD in Pima Indians, a Native American ethnic group with an extremely high prevalence of DKD. In African American men with diabetes, urinary meprin excretion positively correlated with the severity of kidney injury. In mice, meprin activity decreased at the onset of diabetic kidney injury. Several studies have identified meprin targets in the kidney. However, it is not known how proteolytic processing of the targets by meprins impacts the metabolite milieu in kidneys. In the present study, global metabolomics analysis identified differentiating metabolites in kidney tissues from wild-type and meprin-β knockout mice with streptozotocin (STZ)-induced type 1 diabetes. Kidney tissues were harvested at 8 wk post-STZ and analyzed by hydrophilic interaction liquid chromatography ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Principal component analysis identified >200 peaks associated with diabetes. Meprin expression-associated metabolites with strong variable importance of projection scores were indoxyl sulfate, N-γ-l-glutamyl-l-aspartic acid, N-methyl-4-pyridone-3-carboxamide, inosine, and cis-5-decenedioic acid. N-methyl-4-pyridone-3-carboxamide has been previously implicated in kidney injury, and its isomers, 4-PY and 2-PY, are markers of peroxisome proliferation and inflammation that correlate with creatinine clearance and glucose tolerance. Meprin deficiency-associated differentiating metabolites with high variable importance of projection scores were cortisol, hydroxymethoxyphenylcarboxylic acid- O-sulfate, and isovaleryalanine. The data suggest that meprin-β activity enhances diabetic kidney injury in part by altering the metabolite balance in kidneys, favoring high levels of uremic toxins such as indoxyl sulfate and N-methyl-pyridone-carboxamide.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes

2014 ◽  
Vol 92 (8) ◽  
pp. 703-706 ◽  
Author(s):  
David Z.I. Cherney ◽  
Fengxia Xiao ◽  
Joseph Zimpelmann ◽  
Ronnie L.H. Har ◽  
Vesta Lai ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Enzyme Activity ◽  
Angiotensin Converting Enzyme ◽  
Functional Role ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Levels ◽  
Clinical Complications

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4–6 mmol·L–1) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9–11 mmol·L–1) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

scholarly journals Role of Nox2 in diabetic kidney disease

2013 ◽  
Vol 304 (7) ◽  
pp. F840-F848 ◽  
Author(s):  
Young-Hyun You ◽  
Shinichi Okada ◽  
San Ly ◽  
Karin Jandeleit-Dahm ◽  
David Barit ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Type 1 Diabetes ◽  
Kidney Disease ◽  
Systolic Blood Pressure ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Macrophage Infiltration ◽  
Diabetic Kidney

NADPH oxidase (Nox) isoforms have been implicated in contributing to diabetic microvascular complications, but the functional role of individual isoforms in diabetic kidney are unclear. Nox2, in particular, is highly expressed in phagocytes and may play a key inflammatory role in diabetic kidney disease. To determine the role of Nox2, we evaluated kidney function and pathology in wild-type (WT; C57BL/6) and Nox2 knockout (KO) mice with type 1 diabetes. Diabetes was induced in male Nox2 KO and WT mice with a multiple low-dose streptozotocin protocol. Groups were studied for kidney disease after 8 and 20 wk of diabetes. Hyperglycemia and body weights were similar in WT and Nox2 KO diabetic mice. All functional and structural features of early and later stage diabetic kidney disease (albuminuria, mesangial matrix, tubulointerstitial disease, and gene expression of matrix and transforming growth factor-β) were similar in both diabetic groups compared with their respective nondiabetic groups, except for reduction of macrophage infiltration and monocyte chemoattractant protein-1 in the diabetic Nox2 KO mice. Systolic blood pressure by telemetry was surprisingly increased in Nox2 KO mice; however, the systolic blood pressure was reduced in the diabetic WT and Nox2 KO mice by tail-cuff. Interestingly, diabetic Nox2 KO mice had marked upregulation of renal Nox4 at both the glomerular and cortical levels. The present results demonstrate that lack of Nox2 does not protect against diabetic kidney disease in type 1 diabetes, despite a reduction in macrophage infiltration. The lack of renoprotection may be due to upregulation of renal Nox4.

scholarly journals Puerarin attenuates diabetic kidney injury through the suppression of NOX4 expression in podocytes

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Xueling Li ◽  
Weijing Cai ◽  
Kyung Lee ◽  
Bohan Liu ◽  
Yueyi Deng ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Therapeutic Benefit ◽  
Diabetic Kidney ◽  
Protein Levels ◽  
Napdh Oxidase ◽  
Radix Puerariae ◽  
Oxidative Effects ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Abstract Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic nephropathy (DN). Several studies demonstrated that puerarin, the active compound of radix puerariae, reduces diabetic injury in streptozotocin (STZ)-induced diabetic rodent models. However, as STZ injection alone results in mild kidney injury, the therapeutic benefit afforded by puerarin in DN remained inconclusive. Thus we sought to clarify the role of puerarin by employing an accelerated DN model, STZ-induced diabetes in the endothelial nitric oxide synthase-null (eNOS−/−) mice. Puerarin treatment of diabetic eNOS−/− mice significantly attenuated albuminuria and diabetic kidney injury, which were associated with reduced oxidative stress and reduced NAPDH oxidase 4 (NOX4) in glomeruli of diabetic eNOS−/− mice. Puerarin treatment of murine podocytes culture in high glucose conditions led to reduced superoxide production and NOX4 expression. We further determined that that puerarin treatment increased both mRNA and protein levels of SIRT1 in podocytes and that puerarin led to SIRT1-mediated deacetylation of NF-κB and suppression of NOX4 expression. Our findings confirm the renoprotective effects of puerarin in an experimental model of advanced DN and provide a molecular mechanism by which puerarin exerts the anti-oxidative effects in podocytes  in the diabetic milieu.

The Role of Secrecy and Disclosure in Type 1 Diabetes Adherence and Glycemic Control

2013 ◽  
Author(s):  
P. Osborn ◽  
C. A. Berg ◽  
A. E. Hughes ◽  
P. Pham ◽  
D. J. Wiebe
Keyword(s):  
Type 1 Diabetes ◽  
Glycemic Control

Investigating the Role of CD137 Ligand in the Pathogenesis of Type 1 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 317-OR
Author(s):  
BARDEES FODA ◽  
MATTHEW H. FORSBERG ◽  
ASHLEY E. CIECKO ◽  
KEVIN W. MUELLER ◽  
ARON GEURTS ◽  
...  
Keyword(s):  
Type 1 Diabetes
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