There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-κB ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-β and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice.
Together, it is concluded that the obstructive nephropathy has defective effects on bone, and the underlying mechanisms are the reduction of bone formation and the increase of bone resorption, which is mediated, at least partially through local angiotensin II signalling.
Our previous study showed the early molecular responses of bone in response to obstructive nephropathy in a unilateral ureteral obstruction (UUO) mouse model. Here, we addressed the changes in trabecular bone properties at greater trochanter, the proximal and the distal metaphysis of femur in UUO mice. The male mice were subjected to UUO (n510) or sham operation (n510). All mice were killed on day 7 after the surgical operation. The micro-computed tomography (micro-CT) analysis for different femoral trabecular bone sites demonstrated pathological alterations of trabecular bone mass and micro-networks at greater trochanter as shown by decreases in bone mineral density/bone volume (P,0.05) and trabecular number (P,0.05) and increases in trabecular separation (P,0.01) and bone surface/bone volume (P,0.05) in UUO mice. The present study demonstrates that UUO-induced unilateral obstructive nephropathy has markedly detrimental effects on the trabecular trochanter of the femur. 1 The TMV system provides relevant information and is widely used to evaluate CKD patient bone health; 2 however, this information should be expanded to include cancellous bone architecture.Unilateral ureteral obstruction (UUO) induces damage in the unilateral obstructed kidney and is a well-established model of tubulointerstitial kidney fibrosis. 3 We previously reported changes in the renal expression of vitamin D metabolic enzymes and changes in calcium transporter abundance following obstructive nephropathy in mice subjected to UUO 4 and demonstrated early molecular responses of bone to unilateral obstructive nephropathy in the UUO model. 5 However, associated with the pathological alterations of vitamin D metabolism and the expression of genes involved in bone metabolism, whether trabecular bone microstructure would deteriorate in UUO mice remained to be clarified.The availability of three-dimensional (3D) measuring techniques opens new avenues to analyse the biological properties of bone. In this study, femoral trabecular bone parameters were determined by microcomputed tomography (micro-CT) to qualitatively illustrate the alterations of bone properties in mice that were subjected to unilateral obstructive nephropathy.
The effects of urinary-tract obstruction on renal function have been clarified. However, there is little known about the change of renal vitamin D metabolic enzyme expression and vitamin D-dependent calcium transporting proteins expression in obstructive nephropathy. The male mice were subjected to unilateral ureteral obstruction (n = 10) or sham operation (n = 10). All mice were killed on day 7 after the surgical operation. Kidney sections were stained with Masson's trichrome and gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR. The obstructed kidney exhibited interstitial fibrosis as shown by the strong collagen deposition in the interstitium. Quantitative PCR results showed the increase of 1-OHase (P < 0.001) mRNA expression and the decrease of 24-OHase (P < 0.01), CaBP-9k (P < 0.01) and CaBP-28k (P < 0.01) mRNA expression in obstructed kidney as compared to that of the Sham group. In addition, the mRNA expression of 1-OHase and CaBP-9k was significantly increased and decreased, respectively, in obstructed kidney as compared to that of the contra-lateral kidney in unilateral ureteral obstruction (UUO) mice. Together, the present finding supports the hypothesis that the ureteral obstruction leads to the alteration of renal vitamin D metabolic enzyme expression and calcium transporter abundance, which may secondarily induce the abnormality of vitamin D endocrine system and bone health.
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