Kidney Week

Abstract: SA-PO321

Targeted Inhibition of Calpain-1 and -2 Activities Improves the Progression of Proteinuric Kidney Disease in Mice Following Podocyte Injury

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Tian, Xuefei, Yale University School of Medicine, New Haven, Connecticut, United States

Xuefei Tian,

• Inoue, Kazunori, Yale University School of Medicine, New Haven, Connecticut, United States

Kazunori Inoue,

• Pedigo, Christopher E., Yale University School of Medicine, New Haven, Connecticut, United States

Christopher E. Pedigo,

• Ishibe, Shuta, Yale University School of Medicine, New Haven, Connecticut, United States

Shuta Ishibe,

Background

We have previously shown that calpain activation occurs in mice glomerular injury models and in urine samples of proteinuric patients with FSGS. However, calpain’s function in podocyte biology has not been fully elucidated. This study examines whether the decrease in calpain-1/-2 activities, by calpain inhibitor or deletion of podocyte-associated CAPN4 improves the progression of mice podocyte injury.

Methods

Using the proteinuric models Tln1^fl/fl Podcin-Cre mice (Germline Talin1 podocyte knockout mice, Tln1 KO) and Doxycycline inducible Tln1^fl/fl Pod-rtTA TetO-Cre mice (iTln1 KO), inhibiting calpain-1/-2 activities with calpain inhibitor III (CI) was examined for albuminuria, histological changes, and kidney function. Furthermore, a mouse model with podocyte-specific deletion of CAPN4 was generated abrogating both calpain-1/-2 activities. We investigated the above changes on the Tln1^fl/fl CAPN4^fl/fl Podcin-Cre mice (Tln1+CAPN4 DKO) and Tln1^fl/fl Pod-rtTA TetO-Cre mice (iTln1+CAPN4 DKO).

Results

Treatment of Tln1 KO mice with CI (30mg/kg B.W/day, i.p) was started at 2 weeks of age when robust albuminuria was already present. At 8 weeks, significantly reduced albuminuria was observed in the CI treated mice (18229.61±1537.80 vs 12963.55 ±1182.49 µg/mg creatinine). Furthermore, treatment with CI prolonged the survival of the Tln1 KO mice (median survival: 9 weeks vs 4 weeks). Treatment with CI for 4 weeks in the iTln1 KO mice also reduced the degree of albuminuria (4949.55±320.46 vs 3327.87 ±217.28 µg/mg creatinine), improved renal histological lesions, and kidney function. Mice with genetic ablation of CAPN4 in podocytes on the background of Tln1 KO or iTln1 KO reduced the degree of albuminuria (18574.82±1703.31 vs 13398.37 ±1457.07 µg/mg creatinine in Tln1 KO vs Tln1+ CAPN4 DKO at 8 weeks of age; 4335.27±438.42 vs 2445.92 ±367.28 µg/mg creatinine in iTln1 KO vs iTln1+CAPN4 DKO), while also improving the renal histological lesions and kidney function, and leading to the prolonged survival (median survival: 9 weeks vs 4.5 weeks in Tln1+CAPN4 DKO vs Tln1 KO).

Conclusion

Proteinuric kidney disease in both germline Tln1 KO or iTln1 KO mice are attenuated by reduction of calpain-1/-2 activities, thus representing a potential novel therapeutic strategy for the progression of proteinuric kidney disease.

Funding

• NIDDK Support