Kidney Week

Abstract: TH-PO0387

Dynein-Facilitated Biosynthetic Sorting of Nephrin to the Ubiquitin-Proteasome System: A Targetable Pathway for Diabetic Podocytopathy

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Williquett, Jillian, University of Iowa Health Care, Iowa City, Iowa, United States

Jillian Williquett

• Allamargot, Chantal, University of Iowa Health Care, Iowa City, Iowa, United States

Chantal Allamargot, PhD

• Rooney, Faith F., University of Iowa Health Care, Iowa City, Iowa, United States

Faith F. Rooney

• Steinbach, Emily JS, University of Iowa Health Care, Iowa City, Iowa, United States

Emily JS Steinbach, PhD

• Sun, Hua, University of Iowa Health Care, Iowa City, Iowa, United States

Hua Sun, MD, PhD

Background

Diabetic nephropathy is a leading cause of kidney failure but lacks effective therapeutics. Our research demonstrated that hyperglycemia upregulates dynactin 1 (Dcnt1), a cytoplasmic dynein activator. Enhanced dynein promotes postendocytic sorting of nephrin to lysosome through HDAC6, causing nephrin loss and diabetic podocytopathy (DP). INF2-mediated genetic podocytopathy identified dynein-dependent trafficking of nephrin to the ubiquitin proteasome system (UPS) via PI31. We hypothesized that diabetes enhances dynein-mediated biosynthetic sorting of nephrin to the UPS, and dynein inactivation protects podocytes by preventing UPS degradation of newly synthesized nephrin.

Methods

In Streptozotocin (STZ)-induced diabetic mice with podocyte-specific Dctn1 knockout (KO), scanning electron microscopy and immunofluorescent staining were used to assess podocytopathy and dynein-mediated nephrin trafficking. To assess the role of dynein trafficking and UPS degradation of biosynthetic sorting of nephrin, the homeostasis of SNAP-nephrin was examined in podocytes under hyperglycemic (HG) vs. normoglycemic (NG) conditions, with or without Ciliobrevin D, a dynein inhibitor, or Bortezomib, a proteasome inhibitor.

Results

DP in STZ mice was characterized by reduced slit diaphragm (SD) density (29.03% vs. 33.5%), increased glomerulosclerosis (*12.98% vs 0.98%), corroborating with elevated Dctn1 (*8.68% vs. 1.15%) and nephrin loss (*15.32% vs. 29.11%). Podocyte-specific Dctn1 KO protected against diabetic injury restoring SD density (*33.33% vs. 29.03%), preserving nephrin protein (*28.82% vs. 15.32%), and reducing glomerulosclerosis (*0.48% vs 12.98%) *p<0.05 vs. control, n=5. The severity of podocytopathy correlated positively with dynein-mistrafficking of nephrin (R²=0.7865, p<0.0001).
Using surface and cytosolic-SNAP substrates, we demonstrated impaired surface delivery of newly synthesized nephrin in HG podocytes, reversible by Ciliobrevin D or Bortezomib. These findings indicate dynein-dependent trafficking and proteasomal degradation contribute to the loss of biosynthetically sorted nephrin in diabetes.

Conclusion

We identified dynein-mediated trafficking as a critical mechanism promoting UPS degradation of newly synthesized nephrin in diabetic podocytes, which represents novel therapeutic strategies for preserving SD integrity and preventing DP.

Funding

• NIDDK Support