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

TL;DR

This study shows that lacking PTP1B reduces kidney damage in diabetic mice with eNOS deficiency, possibly by improving insulin signaling and reducing stress in kidney cells.

Contribution

The study reveals a novel protective role of PTP1B deficiency in diabetic kidney disease linked to eNOS deficiency.

Findings

PTP1B deficiency reduced albuminuria and glomerular injury in diabetic eNOS-deficient mice.

Podocyte numbers and nephrin expression were higher in DKO mice compared to eNOSKO mice.

sXBP-1 increased and CHOP decreased in DKO podocytes, suggesting reduced ER stress.

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.

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