Vascular effects of parathyroid hormone and parathyroid hormone‐related protein in the split hydronephrotic rat kidney.

Endlich, Karlhans; Massfelder, Thierry; Helwig, Jean-Jacques; Steinhausen, M.

doi:10.1113/jphysiol.1995.sp020599

Cited by 41 publications

(25 citation statements)

References 36 publications

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“…Further effects that may affect progression are the release of renin induced by PTH (40,41). PTH has vasodilatory effects on preglomerular vessels, while efferent arterioles are constricted, presumably secondary to renin release (42). To what extent PTH also has direct effect on renal cells in vivo is uncertain, but such actions of PTH and PTHrp have been demonstrated in cultured human mesangial cells (43).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata¹,

Ritz²,

Odoni³

et al. 2003

Journal of the American Society of Nephrology

139

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Abstract. In renal failure, parathyroid hormone (PTH) is not only involved in the genesis of disturbed calcium/phosphate metabolism and ostitis fibrosa; it is also a permissive factor in the genesis of hypertension, cardiovascular damage, and dyslipidemia. The allosteric activator of the calcium sensing receptor NPSR-568 (R-568) has been shown to reduce the serum intact PTH (iPTH) concentration in uremic rats. It was the purpose of this study in subtotally nephrectomized (SNX) rats to compare pharmacologic abrogation of secondary hyperparathyroidism by R-568 with parathyroidectomy (PTX). The effects on progression of renal failure, BP, and lipid and structural parameters of kidney and heart were studied. Four groups of male SD-rats were studied: (1) sham-operated ϩ vehicletreated rats (controls); (2) SNX ϩ vehicle-treated rats (SNX); (3) parathyroidectomized SNX ϩ vehicle-treated rats (SNXϩPTX); and (4) SNX ϩ calcimimetic R-568 -treated rats (SNXϩR-568). R-568 (50 mol/kg per d) was administered by gavage. Eight weeks after SNX, serum creatinine concentration, urinary albumin excretion, BP, and serum LDL-cholesterol concentration were significantly lower in both R-568 -treated and parathyroidectomized SNX compared with vehicletreated SNX. In addition, structural abnormalities of the kidney (glomerulosclerosis, tubulointerstitial changes) and the heart (interstitial fibrosis, capillary length density, arteriolar wall thickness) were significantly less pronounced than in vehicletreated SNX. It is concluded that in experimental renal failure abrogation of hyperparathyroidism by administration of a calcimimetic or PTX similarly attenuates progression of renal failure. Furthermore, it interferes with the development of cardiovascular risk factors and cardiac remodeling.Secondary hyperparathyroidism (sHPT) is a known complication of chronic renal failure. Elevated concentrations of parathyroid hormone (PTH) play a role not only in the pathogenesis of renal bone disease (1,2), but also in the development of cardiovascular risk factors such as disturbed lipid metabolism (3,4), glucose intolerance (5), and hypertension (6 -8). Parathyroidectomy (PTX) attenuates progression of renal failure in subtotally nephrectomized rats (SNX) on a high protein (9) or high phosphate (10,11) diet. sHPT is also known to play an important role in the development of structural abnormalities of the heart in renal failure, including left ventricular hypertrophy, interstitial fibrosis, and arteriolar wall thickening of the heart (7,(12)(13)(14).Allosteric activators of the calcium sensing receptor, e.g., NPSR-568 (R-568), reduce PTH secretion in rats or patients with primary and secondary hyperparathyroidism (15-20).There is no information on whether calcimimetics also affect abnormalities of uremia other than calcemia, phosphatemia (21), PTH concentrations (22), and skeletal abnormalities (17).Therefore, it was the purpose of this study to compare the effects of the calcimimetic R-568 and of parathyroidectomy on progression of renal failure, ...

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Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata¹,

Ritz²,

Odoni³

et al. 2003

Journal of the American Society of Nephrology

139

View full text Add to dashboard Cite

show abstract

“…Massfelder et al [22] Endlich et al [21] Bosch et al [16] PTHrP and its receptor in the renal tubule autocrine and paracrine system Philbrick et al [3] Lee et al [12] Largo et al [13] PTH and PTHrP have the same effect in the tubular epithelium stimulate 1·-hydroxylase activity inhibition of Na + /H + exchange calcium and phospate transport Everhart-Caye et al [23] Maeda et al [4] Philbrick et al [3] Experimental nephropathies cyclosporine nephrotoxicity tubuloinstertitial nephropathy acute renal failure García-Ocaña et al [38] Largo et al [13] Soifer et al [33] Santos et al [40] On the other hand, despite the similarities in actions of these peptides in bone and kidney, there are some differences in their biological activities. For example, while one of the mid-region fragments of PTHrP has the ability to increase calcium flux in bovine placenta [5], the N-terminal portion of PTHrP is required for the inhibition of apical Na + /H + exchange in opossum kidney cells [2].…”

Section: Introductionmentioning

confidence: 99%

Parathyroid Hormone-Related Protein as a Renal Regulating Factor

et al. 2001

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Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar biological effects through the PTH/PTHrP receptor. Less is known about the physiological role of PTHrP, which was first identified as the agent of the humoral hypercalcemia of malignancy. Despite the widespread production of PTHrP in healthy individuals, the concentration of the protein is below the detectable limit of current assays, suggesting that PTHrP normally functions locally in an autocrine or paracrine manner. Thus, some differences in their biological activities have been described and they may be related to the presence of different receptors. In this regard, a second receptor that binds selectively to PTH has also been found. Recent studies have demonstrated the expression of both PTH/PTHrP receptor and protein in the renal glomeruli. Moreover, there are convincing data that support a direct role of PTH and PTHrP in modulating renal blood flow and glomerular filtration rate. This multifunctional protein, PTHrP, also has a proliferative effect on both glomerular mesangial cells and tubular epithelial cells. Increases in the expression of PTHrP have been observed in several experimental models of nephropathies, suggesting that PTHrP upregulation is a common event associated with the mechanism of renal injury and repair.

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“…PTHrP is a potent vasodilator of the renal vasculature acting via the PTH/PTHrP receptor [15, 16]. Similarly to podocytes, the PTH/PTHrP receptor couples only to the cAMP pathway in vascular smooth muscle cells [12, 14].…”

Section: Discussionmentioning

confidence: 99%

“…The PTH/PTHrP receptor couples to the adenylyl cyclase and the phospholipase C pathway in many cells [11, 12, 13], except for smooth muscle cells where the PTH/PTHrP receptor couples to the adenylyl cyclase pathway only [12, 14]. PTHrP(1–36) induces relaxation of smooth muscle and potently dilates the renal vasculature [15, 16]. Interestingly, in the glomerulus, PTHrP and the PTH/PTHrP receptor are expressed only in podocytes under physiological conditions [3, 4, 6, 7, 8, 9].…”

Section: Introductionmentioning

confidence: 99%

Expression and Signaling of Parathyroid Hormone-Related Protein in Cultured Podocytes

Endlich

Nobiling

Kriz

et al. 2001

Nephron Exp Nephrol

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Podocyte function appears to be regulated by vasoactive factors. In vivo podocytes express parathyroid hormone-related protein (PTHrP), the N-terminal fragment of which has vasoactive properties. Since the signaling pathway(s) of PTHrP(1–36) are unknown in podocytes, differentiated cells of a conditionally immortalized mouse podocyte cell line were studied. Gene expression of PTHrP and the PTH/PTHrP receptor was investigated by RT-PCR; protein distribution of PTHrP was examined by immunofluorescence. Accumulation of cAMP was determined by an enzyme immunoassay; [Ca²⁺]_i was measured by fura-2 ratio imaging. PTHrP and PTH/PTHrP receptor mRNA was detected in differentiated podocytes. Immunoreactive PTHrP exhibited a granular distribution in the cytoplasm of differentiated podocytes. With regard to the signaling pathway(s) of PTHrP(1–36), a concentration-dependent increase of cAMP levels with an EC₅₀ value of 4 ± 2 nM was found. PTHrP(1–36) (1 µM) increased cAMP levels 5.5 ± 1.1-fold above baseline as compared with a 25.4 ± 4.2-fold increase in response to forskolin (10 µM). The PTH/PTHrP receptor antagonist PTHrP(7–34) significantly diminished the PTHrP(1–36)-induced cAMP increase. While superfusion of podocytes with bradykinin (100 nM) increased [Ca²⁺]_i, PTHrP(1–36) (100 nM) was without effect on [Ca²⁺]_i. However, PTHrP(1–36) attenuated the bradykinin-induced increase in [Ca²⁺]_i. Our results suggest that PTHrP is an autocrine hormone in podocytes, which selectively activates the cAMP pathway through the PTH/PTHrP receptor.

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Vascular effects of parathyroid hormone and parathyroid hormone‐related protein in the split hydronephrotic rat kidney.

Cited by 41 publications

References 36 publications

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Parathyroid Hormone-Related Protein as a Renal Regulating Factor

Expression and Signaling of Parathyroid Hormone-Related Protein in Cultured Podocytes

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