Abstract: TH-OR115
Rescue of Reno-Protective BMP7 by Low-Dose Hydralazine Protects Functional Parenchyma with Restoration of Solute and Solvent Transporters
Session Information
- Scarred for Life?
November 02, 2017 | Location: Room 394, Morial Convention Center
Abstract Time: 05:54 PM - 06:06 PM
Category: Chronic Kidney Disease (Non-Dialysis)
- 308 CKD: Mechanisms of Tubulointerstitial Fibrosis
Authors
- Tampe, Bjoern, University Medical Center Goettingen, Goettingen, Germany
- Tampe, Desiree, University Medical Center Goettingen, Goettingen, Germany
- Mueller, Gerhard A., University Medical Center Goettingen, Goettingen, Germany
- Zeisberg, Michael, University Medical Center Goettingen, Goettingen, Germany
Background
CKD progression remains an unsolved problem in clinical Nephrology since approaches to reverse or repair chronic renal injury are not yet available. BMP7 and its agonists are among leading compounds currently under clinical testing and widely accepted to facilitate regeneration of the injured kidney, ultimatively associated with attenuation of disease progression. The impact of restoring intrarenal BMP7 with regard of renal excretory function on a molecular level remains elusive.
Methods
In multiple mouse models of acute (moderate IRI), acute-on-chronic (severe IRI) and chronic kidney disease (UUO, 5/6 Nx, FAN, NTN), dynamic regulation of BMP7 and signaling (pSmad1/5/8) were analyzed by qRT-PCR, Western blotting and immunostaining. Furthermore, BMP7 promoter methylation was assessed by MeDIP in cohorts of mice treated with low-dose Hydralazine and corresponding cell culture models of EMT program in TECs. Finally, impact on expression of solute and solvent transporters was analyzed by qRT-PCR, immunostaining and functional monitoring of transporter function.
Results
Based on a genome-wide transcriptional expression dataset for bioactive small molecules, transcriptional induction of BMP7 was among top induced candidate genes in response to Hydralazine. Low-dose Hydralazine mediates TET3-dependent normalization of BMP7 promoter methylation in multiple rodent CKD models and human cell lines. On a mechanistic level, transcriptional induction of reno-protective BMP7 attenuates intratubular EMT program commonly observed during CKD progression, ultimatively associated with protection from G2/M arrest of TECs and attenuation of renal fibrogenesis. We provide evidence that protection of functional parenchyma restores solute and solvent transporter function, including AQP1, AQP3 and Na+/K+-ATPase, supporting a protective role also for renal excretory function on a molecular level. Based on existing transciptional profiling datasets, decline of renal excretory function is commonly associated with loss of intrarenal BMP7 expression, suggesting that reno-protection mediated by Hydralazine may also have promise among CKD patients.
Conclusion
In summary, low-dose Hydralazine induces reno-protective BMP7 and protects functional parenchyma with restoration of solute and solvent transporters.