Elsevier

Pharmacological Research

Volume 106, April 2016, Pages 87-91
Pharmacological Research

Review
Phosphate and FGF23 in the renoprotective benefit of RAAS inhibition

https://doi.org/10.1016/j.phrs.2016.02.015Get rights and content

Abstract

Renin angiotensin-aldosterone system (RAAS) blockade is a mainstay of chronic kidney disease (CKD) treatment given its beneficial effects on proteinuria, nephroprotection, heart disease and global mortality.

The FGF23/Klotho/phosphate axis is crucial for phosphate excretion. During CKD, loss of Klotho, decreased phosphate excretion and FGF23 elevation are early events contributing both to renal disease progression and to cardiovascular complications. Experimental evidence suggests that Klotho replacement may improve renal and cardiovascular disease during CKD.

Recent evidence suggests that both RAAS activation and proteinuria decrease Klotho expression and lead to phosphate retention and FGF23 elevation. In opposition RAAS blockade may reverse Klotho loss during CKD in both experimental and human studies, with direct and indirect expected beneficial effects on the kidney and cardiovascular system. This effect of RAAS blockade on the FGF23/Klotho/phosphate axis may participate in explaining some of the beneficial effects of these drugs during CKD.

In this article we review the evidence linking RAAS blockade to modulation of the FGF23/Klotho/phosphate axis and the beneficial effects of these regulations.

Introduction

ACE inhibitors and AT1 receptor Blockers (ARBs) display renoprotective effects in proteinuric diabetic and nondiabetic kidney diseases. Renin-angiotensin-aldosterone system (RAAS) blockade reduces proteinuria by decreasing intraglomerular pressure via a vasodilatory effect on the afferent and efferent glomerular arterioles [1]. This effect is significant (average 30%) and independent of the cause of proteinuria. ACE inhibitors’ and ARB’s nephroprotective properties on long term renal function have been demonstrated in several populations of proteinuric chronic kidney disease (CKD) [2], [3], [4], [5], [6] patients. In addition these drugs increase survival and improve heart function during left ventricular dysfunction [7], [8], [9], [10]. Finally, RAAS blockade has been recently associated to decreased mortality in patients with CKD [11]. The FGF23/Klotho system regulates phosphate excretion and plays a major role in mineral metabolism [12]. Alterations of mineral metabolism are early events in CKD and contribute both to renal disease progression and to CKD extrarenal complications (mostly cardiovascular). Both proteinuria and RAAS have been described to interact with the FGF23/Klotho/phosphate system. In this article, we first introduce the FGF23/Klotho/phosphate system in CKD, then review the evidence linking proteinuria and RAAS to the FGF23/Klotho system and finally discuss the potential beneficial role of RAAS inhibition via FGF23/Klotho and phosphate regulation.

Section snippets

The FGF23/Klotho/phosphate axis during chronic kidney disease (CKD)

Major modifications of the FGF23/Klotho/phosphate axis occur already early in the course of CKD and influence both renal and extrarenal evolutions of the disease [13], [14]. The anomalies of phosphate excretion are usually defined as CKD-mineral and bone disease (CKD-MBD). In general, the more advanced the CKD, the more severe the CKD-MBD. Epidemiologically, there are clear evidence linking perturbations of mineral metabolism to cardiovascular mortality and renal disease progression.

RAAS inhibition, proteinuria and FGF23/Klotho/phosphate axis

ACE inhibitors and ARBs alleviate the deleterious effects of RAAS activation. Their renoprotective effect is demonstrated in diabetic and non diabetic proteinuric nephropathies and appears to result mainly from proteinuria reduction but also from inhibition of Angiotensin II production or activity [59], [60], [61], [62]. In addition, RAAS blockade is beneficial in heart failure through several effects [63]. Finally, recent evidence demonstrates that ACE inhibition decreases mortality in CKD

Conclusions and perspectives

There are several points of potential interactions between RAA system and FGF23/Klotho axis. RAAS blockade appears to rescue Klotho downregulation observed in various types of CKD models and in humans. This effect may be linked to a direct consequence of RAAS inhibition and/or to reduction of proteinuria and its subsequent improvement in Klotho expression and tubular FGF23 resistance. These observations are important since FGF23/Klotho axis dysregulation appears to play important roles in CKD

Conflict of interest

We report no conflict of interest.

Acknowledgments

SdS is funded by grants from the Swiss National Science foundation, the National Center for Competence in Research NCCR. Kidney.ch, the Von Meissner Foundation and Schmidheiny Foundation.

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