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 HIF-2α-IN-1 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 diabetic rats. 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 YHO-13351 (free base) 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-targ