Abstract: SA-PO120
The Iron-Klotho-VDR Axis Is a Major Determinant of Proximal Convoluted Tubule Injury in Haptoglobin 2-2 Genotype Diabetic Nephropathy Patients and mice
Session Information
- Diabetic Kidney Disease: Basic - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Nakhoul, Farid M., Baruch padeh Poriya Medical center, Tiberias, Israel
- Farber, Evgeny, Baruch Padeh Poriya Medical Center, Tiberias, Northern, Israel
- Nakhoul, Nakhoul, Baruch Padeh Poriya Medical center, Lower Galille, Israel
- Dahan, Inbal, Baruch Padeh Poriya Med Ctr, Tiberias, Israel
Background
The haptoglobin (Hp) genotype (1-1, 2-2) is a major determinant of DN progression in DM patients. Hp 2-2 DM patients & mice have increased iron deposits in the PCT, leading to renal injury. The mechanism of the PCT injury in DN remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein.
Increased renal iron deposits in the PCT of Hp 2-2 DN may affects α-klotho-Vitamin D receptor axis and exacerbates PCT injury
Methods
Seven-week-old male mice were made diabetic by IP injection of 50 mg/kg of STZ per day for 5 consecutive days. Mice were sacrificed after a DM duration of 2 months. DM mice with Hp 2-2 and Hp1-1, DM and non-DM CKD patients were included. Kidney biopsies from mice and patients were subject to immunohistochemistry (IHC) and PAS staining . Mice kidney lysates were subjected to western blot analysis.
Results
A marked accumulation of iron deposits in the renal PCT of Hp 2-2 DM mice compared to Hp 1-1 DM or with Hp 2-2 non-DM mice. The expression of renal α-klotho was reduced significantly in the PCT of DN mice and patients with the Hp 2-2 genotype in mice and humans compared to DM Hp 1-1 genotype in mice and CKD humans
Western blot analysis of the mice renal lysates show that VDR renal expression was decreased significantly in the PCT of DN Hp 2-2 sections compared to DM Hp 1-1 genotype. The renal expression of 1-α-hydroxylase was increased significantly in DN mice with Hp 2-2 genotype compared with DM Hp 1-1 genotype
Conclusion
The Iron-Klotho-VDR axis is a key player in themechanism of iron-mediated PCT injury in DN mice and patients with Hp 2-2 genotype
Increased iron deposits in the PCT of Hp 2-2 genotype can lead to reduced renal expression of α-klotho and VDR protein level and PCT injury.
Targeting the iron-klotho-Vit. D axis in DM Hp 2-2 patients may explore new ideas on pathog. and TX of early
DN