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Prior work demonstrated that Phlpp1 deficiency alters limb length and bone mass, but the cell types involved and requirement of Phlpp1 for this effect were unclear. To understand the function of Phlpp1 within bone-forming osteoblasts, we crossed Phlpp1 floxed mice with mice harboring type 1 collagen (Col1a1 2.3kb )-Cre. Mineralization of bone marrow stromal cell cultures derived from Phlpp1 cKO Col1a1 was unchanged, but levels of inflammatory genes (eg, Ifng , Il6 , Ccl8 ) and receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratios were enhanced by either Phlpp1 ablation or chemical inhibition. Micro-computed tomography of the distal femur and L 5 vertebral body of 12-week-old mice revealed no alteration in bone volume per total volume, but compromised femoral bone microarchitecture within Phlpp1 cKO Col1a1 conditional knockout females. Bone histomorphometry of the proximal tibia documented no changes in osteoblast or osteoclast number per bone surface but slight reductions in osteoclast surface per bone surface. Overall, our data show that deletion of Phlpp1 in type 1 collagen-expressing cells does not significantly alter attainment of peak bone mass of either males or females, but may enhance inflammatory gene expression and the ratio of RANKL/OPG. Future studies examining the role of Phlpp1 within models of advanced age, inflammation, or osteocytes, as well as functional redundancy with the related Phlpp2 isoform are warranted. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Earlier studies in diabetic animal models or ex vivo from diabetics suggest a deficiency in prostacyclin (PGI2) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), which stimulates angiogenesis, mitogenesis, and inhibits renin secretion. We studied the urinary excretion rate of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and 12-HETE in controls and 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with normal renal function and those with micro- or macroalbuminuria/hyporeninemic hypoaldosteronism (HH). The 2 eicosanoids were measured in urine using previously described high pressure liquid chromatography and RIA methods. Normal subjects and patients with NIDDM and microalbuminuria were infused with low dose calcium infusions that stimulate prostacyclin production in normal subjects. The PGI2 excretion rate of NIDDM patients with normal renal function was not different from that of controls (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in those with microalbuminuria (75 +/- 10) and in macroalbuminuria patients (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetics with normal renal function as well as in those with micro- or macroalbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 +/- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI2, but increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI2 (as previously reported), but had increased 12-HETE. HETE/PGI2 ratios further demonstrated these changes in the various groups. In a nondiabetic hypertensive microalbuminuria group, 12-HETE excretion was normal (73 +/- 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HETE is increased early in the diabetic process, whereas PGI2 production is progressively impaired in NIDDM. These changes may play a role in the vascular disease of diabetes and partially explain the HH syndrome.

This study explored the role of the dopamine-2 receptor (DA2) in the control of renal blood flow (RBF) and the influence of variations in sodium intake. These relationships have not been previously defined in man. Seven normotensive male subjects underwent a low dose dopamine (DA) infusion (1 microgram/kg.min) for 3 h, known to activate both DA1 and DA2 receptors. The effect of DA2 receptor on renal hemodynamics was studied using a relatively specific DA2 blocker [domperidone (DOM); 60 mg, orally] alone and with a DA infusion. Systemic and renal hemodynamics parameters were measured noninvasively. Urinary prostacyclin was measured in 3-h urine specimens, obtained during the DA infusion. The DA infusion increased RBF and prostacyclin during both normal and high salt diets, but this effect was attenuated on a low salt diet. DOM alone significantly reduced basal RBF during normal (1304 +/- 48 vs. 1175 +/- 45 mL/min.1.73 m2; P < 0.01) and low salt diets (1402 +/- 80 vs. 1220 +/- 101 mL/min.1.73 m2; P < 0.02), but was without effect during high sodium intake. DOM had no effect on prostacyclin excretion at any level of salt intake. These results suggest that both DA1 and DA2 are activated in renal vessels by DA, and that DA2 receptors play a role in the renal vasodilating action of DA. Changes in sodium balance alter the actions of the two receptors (DA1 and DA2) in a coordinated fashion in the regulation of RBF.

A low dose of dopamine (1 microgram/min/kg) infused for 3 h, which is without systemic hemodynamic effects in normal subjects, increased the renal blood flow and renal production of prostacyclin (PGI2). This action was blocked by metoclopramide as well as by either of two cyclooxygenase (CO) blockers, but effects were not altered by administration of the alpha 1 blocker prazosin. Much of the effect of dopamine (DA) is apparently via the DA1 receptor, since fenoldopam (0.1 microgram/min/kg) reproduced these actions. However, although fenoldopam increased glomerular filtration rate and urinary Na+, CO blockers were without effect. In contrast neither DA or fenoldopam infusions changed either renal blood flow or PGI2 in a group of patients with essential hypertension. Renin secretion was shown to be increased via DA1 receptor activation both in humans and rat renal tissue. The DA2 receptor may also play a role since domperidone can reduce renal blood flow.