ReviewPhosphate and FGF23 in the renoprotective benefit of RAAS inhibition
Graphical abstract
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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