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Updated: May 5, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Substantially Attenuates Glomerular Injury in Endothelial Nitric
Daisuke Katagiri1, Shinya Nagasaka1, Keiko Takahashi1
1Nephrology, Vanderbilt University Medical Center, Nashville, USA.
Abstract:
Background Deficiency of endothelial nitric oxide synthase (eNOS) accelerates diabetic nephropathy (DN); however, the underlying mechanisms are incompletely understood. Given that nitric oxide inactivates protein tyrosine phosphatase 1B (PTP1B), a critical negative regulator of insulin signaling, we hypothesized that eNOS deficiency activates PTP1B; this reduces insulin signaling and worsens glomerular injury in DN. Methods PTP1B/eNOS double knockout (DKO) mice were generated and compared to eNOS knockout (KO) mice. Diabetes was induced at eight weeks of age by low-dose streptozotocin injections, and phenotypic analyses were performed at 10 and 22 weeks after streptozotocin administration. Results Although no differences were found in blood glucose, blood pressure, or left kidney weight-to-body weight ratio between the diabetic DKO and eNOSKO mice, albuminuria was largely reduced in DKO mice. Histological, Immunofluorescence, and immunohistochemical investigations showed substantially milder mesangial expansion and mesangiolysis and higher podocyte numbers and nephrin expression in DKO mice. Spliced X-box binding protein 1 (sXBP-1) expression was greatly increased, and C/EBP-homologous protein (CHOP) was decreased in the podocytes of DKO mice. Conclusions PTP1B deficiency substantially reduces glomerular injury in diabetic eNOSKO mice. Enhanced insulin signaling and improved endoplasmic reticulum (ER) stress in podocytes were suggested as a possible mechanism.
Insights
Endothelial nitric oxide synthase (eNOS) deficiency worsens diabetic nephropathy (DN) by activating protein tyrosine phosphatase 1B (PTP1B). However, PTP1B deficiency significantly reduces glomerular injury in diabetic eNOS knockout mice.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Endothelial nitric oxide synthase (eNOS) deficiency exacerbates diabetic nephropathy (DN), but mechanisms remain unclear.
- Nitric oxide inactivates protein tyrosine phosphatase 1B (PTP1B), a key negative regulator of insulin signaling.
- We hypothesized eNOS deficiency activates PTP1B, impairing insulin signaling and worsening kidney injury in DN.
Purpose of the Study:
- To investigate the role of PTP1B in eNOS deficiency-driven diabetic nephropathy.
- To determine if PTP1B deficiency ameliorates glomerular injury in the absence of eNOS.
Main Methods:
- Generated and analyzed PTP1B/eNOS double knockout (DKO) mice compared to eNOS knockout (KO) mice.
- Induced diabetes using streptozotocin and performed phenotypic analyses at 10 and 22 weeks.
- Utilized histological, immunofluorescence, and immunohistochemical methods to assess glomerular injury and podocyte markers.
Main Results:
- Diabetic DKO mice showed significantly reduced albuminuria compared to diabetic eNOS KO mice.
- Histological analysis revealed milder mesangial expansion and mesangiolysis in DKO mice.
- DKO mice exhibited higher podocyte numbers, increased nephrin expression, elevated spliced X-box binding protein 1 (sXBP-1), and decreased C/EBP-homologous protein (CHOP) in podocytes.
Conclusions:
- PTP1B deficiency substantially mitigates glomerular injury in diabetic mice lacking eNOS.
- Enhanced insulin signaling and improved podocyte endoplasmic reticulum (ER) stress are potential mechanisms underlying this renoprotective effect.
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