Renal proximal tubule cells: power and finesse

Abstract

The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of the proximal tubule. Yoon et al. demonstrated the intracellular mechanism by which parathyroid hormone (PTH) increases production of 1,25-vitamin D. Activation of PTH receptor 1/cAMP/PKA signaling inhibited salt-inducible kinase 2 (SIK2) and SIK3, which increased CYB27B1 transcription and 1,25-vitamin D production. Replication of these effects with small-molecule SIK inhibitors suggests possible therapeutic applications for patients with disorders characterized by 1,25-vitamin D deficiency. Zhou et al. discovered that proximal tubule glycolysis acts as a phosphate sensor that regulates fibroblast growth factor 23 production in bone. They described several kidney-specific metabolic modifications that enabled glycolysis to be deployed as a phosphate sensor. The provocative results raise intriguing questions with implications for patients with disorders of phosphate homeostasis, including chronic kidney disease.

Figure 1. SIK2/SIK3 regulates 1,25-vitamin D production, and glycolysis acts as a phosphate sensor in proximal tubular epithelia.

PTH binding to its receptor drives cAMP-mediated PKA phosphorylation of SIK2/SIK3. Phosphorylation of SIK2/SIK3 leads to binding of 14-3-3 chaperone proteins that inhibit the constitutive phosphorylation of SIK targets. Inhibition of SIK-mediated phosphorylation liberates cofactor CRTC2 and facilitates its translocation into the nucleus. Nuclear binding of CRTC2 to pCREB at the M1/M21 enhancer leads to increased transcription of CYP27B1 and, via an incompletely understood mechanism, downregulation of CYP24A1. Increased CYP27B1 and decreased CYP24A1 activity in response to PTH or SIK inhibition increases circulating 1,25-vitamin D levels. Through an effect of PTH that is independent of SIK2/SIK3, PTH receptor 1 (PTHR1) activation also reduces phosphate reabsorption via PKC-mediated phosphorylation of scaffolding proteins, which leads to downregulation of NPT2a function in the apical membrane. NPT2a is the entrance pathway for inorganic phosphate that serves as the rate-limiting substrate for GAPDH-catalyzed glycolysis in proximal tubules. Cytosolic NAD⁺ recycling by GPD1 produces G-3-P, which is released into the circulation through an unknown mechanism and stimulates FGF23 production in bone. Closing the feedback loop, binding of FGF23 to FGF receptor–klotho coreceptor complexes leads to downregulation of NPT2a function and increased renal phosphate excretion. Opposing the analogous effects of PTH, FGF23 also inhibits CYP27B1 and stimulates CYP24A1 activity.