Dietary Phosphate Binding and Loading Alter Kidney Angiotensin-Converting Enzyme mRNA and Protein Content in 5/6 Nephrectomized Rats

Abstract

Background: Vitamin D receptor activation with paricalcitol can modulate the transcription of renin-angiotensin system components in the surgical 5/6 nephrectomy rat model (5/6 NX) of chronic renal insufficiency. We tested the hypothesis whether dietary modification of phosphate influences kidney renin-angiotensin system gene expression at the mRNA level in 5/6 NX rats. Methods: Fifteen weeks after surgery, rats were given control diet (0.3% calcium, 0.5% phosphate), phosphate-lowering diet (3% calcium as carbonate) or high-phosphate diet (1.5%) for 12 weeks. Sham-operated rats were on control diet. Results: Blood pressure, plasma phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were increased in remnant kidney rats, whereas creatinine clearance was decreased. Phosphate, parathyroid hormone, glomerulosclerosis, tubulointerstitial damage, and FGF-23 were further elevated by the high-phosphate diet, but were reduced by the phosphate-lowering diet. Plasma calcium was increased with the phosphate-lowering diet and decreased with the high-phosphate diet. Remnant kidney rats on control diet showed upregulated kidney angiotensin-converting enzyme (ACE) and angiotensin (Ang) IV receptor (AT₄) transcription, while ACE2, Ang II type 2 receptor and renin receptor transcription were downregulated in comparison with sham rats. Phosphate-lowering diet reduced whereas high-phosphate diet increased kidney ACE, and these effects were observed at both mRNA and protein levels. Dietary phosphate loading also resulted in lower AT_1a gene transcription. Conclusion: Dietary phosphate loading was associated with elevated kidney ACE expression, increased tissue damage and lower AT_1a transcription in 5/6 NX rats. Phosphate binding with 3% calcium carbonate had opposite effects on ACE and kidney damage.

Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats

“…18,184,185 Extracellular phosphate concentrations have also been associated with increased production of profibrotic mediators and may have a direct stimulatory effect on RAAS. [186][187][188] There is some evidence supporting the role of phosphorus in the pathogenesis of feline CKD. Early studies evaluating phosphate restricted diets showed that cats on restricted diets had reduced evidence of renal histopathological lesions (calcification, fibrosis and inflammatory cell infiltration) compared to cats on a high phosphorus diet.…”

Inactivation of AMPK Mediates High Phosphate-Induced Extracellular Matrix Accumulation via NOX4/TGFß-1 Signaling in Human Mesangial Cells

“…Clinical and experimental data indicate that elevated plasma phosphate (Pi) may contribute to progression of chronic kidney disease (CKD) [1,2,3,4,5] by a not fully elucidated mechanism. In spite of that, the effect of high Pi levels per se on kidney cells may play a role, since it has been shown that addition of higher Pi concentrations to the culture medium of kidney fibroblasts elicits increased extracellular matrix (ECM) production [6].…”

Phosphate Binding Reduces Aortic Angiotensin-Converting Enzyme and Enhances Nitric Oxide Bioactivity in Experimental Renal Insufficiency

“…In addition, functional and structural changes in resistance arteries have been described in both clinical [3] and experimental chronic renal insufficiency (CRI) [4]. Phosphate retention, hypocalcemia, increased fibroblast growth factor 23, and reduced vitamin D levels lead to the development of secondary hyperparathyroidism already at stages 2 and 3 of CRI [5,6], and these factors also influence the remodeling of the vascular wall [7]. In order to manage CRI-induced hyperphosphatemia and hyperparathyroidism, oral phosphate binders are frequently needed [8].…”

“…A key target for the pharmacological inhibition of the renin-angiotensin system is angiotensin-converting enzyme (ACE), which converts angiotensin I (Ang I) to Ang II and degrades kinins [13]. We recently found that dietary phosphate loading was associated with increased kidney ACE expression and tissue damage in the 5/6 nephrectomy (NX) rat model of CRI [5]. In contrast, phosphate binding with 3.0% calcium carbonate reduced kidney ACE and tissue damage [5].…”

“…We recently found that dietary phosphate loading was associated with increased kidney ACE expression and tissue damage in the 5/6 nephrectomy (NX) rat model of CRI [5]. In contrast, phosphate binding with 3.0% calcium carbonate reduced kidney ACE and tissue damage [5]. …”