Protein Tyrosine Phosphatase 1B (PTP1B) Deficiency Substantially Attenuates Glomerular Injury in Endothelial Nitric Oxide Synthase (eNOS)-Deficient Diabetic Mice

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.