The present data would add the kidney as a direct sensor organ that may interfere in phosphate homeostasis via its own FGF23 production. It is noteworthy that the FGF23 co-receptor CPI-613 Klotho is expressed weakly in the proximal tubules -despite the fact that the FGF23 phosphaturic action is substantially exerted at this levelwhereas distal tubules showed more abundant Klotho expression. Two mechanisms have been proposed : either FGF23 acts on proximal tubules via FGFR-Klotho signaling to directly regulate NaPi co-transporters, and/or acts on the distal tubules to induce a paracrine signal to proximal tubules. The putative paracrine factor is the secreted Klotho Crizotinib itself able to directly inhibit NaPi co-transporters and to activate several ion channels in proximal tubules. The significance of the local production of FGF23 is obscure. FGF23 expression might represent an adaptive response to early injury as a mechanism by which the ZDF rat kidney could maintain phosphate homeostasis. Indeed, at 4 months, Klotho was normally expressed in the kidney allowing FGF23 phosphaturic activity to maintain serum phosphate levels similar to those of lean rats. Finding that ZDF rats exhibited a 2fold higher urinary phosphorus excretion than lean rats could also be attributed to a 2-fold increased food intake in ZDF rats. As renal disease progressed, despite the increasing FGF23 levels, fractional phosphorus excretion decreased possibly due to a lower renal Klotho expression and a reduction in functioning nephrons, with the net result of increased serum phosphate levels. Our finding of decreased Klotho expression in the kidney of ZDF 
rats during overt nephropathy is in agreement with findings of decline of renal Klotho both in rodent models of chronic renal damage and patients with CKD. Klotho is a putative aging suppressor, and there is compelling evidence that its depletion is associated with oxidative stress, inflammation, accelerated aging and renal fibrosis. An important observation of the present study is that ramipril therapy, which limited proteinuria and renal damage in ZDF rats, effectively prevented the time-dependent increase of renal FGF23 expression, and almost normalized Klotho expression. A cross talk between the renin-angiotensin-system and Klotho-FGF23 axis has been suggested. Angiotensin II causes renal Klotho loss leading to disrupted FGF23 signaling and reduced phosphaturia. In a model of renal damage characterized by renal RAS activation and Klotho downregulation, the treatment with an angiotensin II type 1 receptor blocker prevented the loss of Klotho expression and ameliorated renal histology. Here, ramipril by recovering renal Klotho expression allowed re-engagement of serum and residual renal FGF23 to exert phosphaturic activity, resulting in normalization of serum phosphate levels in diabeticrats. Ramipril was capable to restore the mRNA expression of NaPi-2a co-transporter to normal levels, which however, did not translate into recovery of the protein on the brush border of proximal tubules. Discrepancy between NaPi-2a co-transporter mRNA and protein expression could be attributable to post-transcriptional events that precluded a full restoration of the protein. This would explain the high level of phosphorus excretion at 8 months in ramipril-treated diabetic rats. In early stage of CKD, elevation of FGF23 represents an appropriate physiological response to prevent hyperphosphatemia. However, with CKD progression, the excess of biologically active FGF23 becomes no longer protective and may instead lead to pathological off-target effects. Elevated circulating levels of FGF23 were associated with vascular dysfunction, atherosclerotic burden and left ventricular hyperthrophy in CKD patients, and FGF23 directly induced hypertrophy of cultured cardiomyocytes. Recently, inflammation has been identified as another potential off-target, in that higher FGF23 levels were independently associated with higher levels of inflammatory markers in patients with CKD. Consistently, here, in ZDF rats the reduction of renal FGF23 production after treatment with ACE inhibitor was paralleled by less infiltrates of inflammatory cells in the renal interstitium. To maximize renoprotection in ZDF rats one could foresee adding other compounds to the ACE inhibitor. In the search for an effective therapy, molecules that have the ability to limit, but not to abrogate FGF23 production would represent a valuable approach. A recent study has shown vascular calcification associated with increased risk of mortality in CKD rats.