Fasting and refeeding associated hormones hijack proximal tubule circadian control mechanisms and regulate glucose reabsorption via the Nrf1/Sglt2 pathway

Blood glucose levels are controlled by temporal changes in glucose tolerance and insulin sensitivity. Besides pancreas and liver, the kidneys play an important role in blood glucose homeostasis by limiting urinary glucose loss. We have shown that circadian clock genes, such as Clock and Bmal1, regulate the circadian rhythm of plasma lipids—mutant of Clock increase lipid and glucose absorption. However, how clock genes regulate kidney function to control blood glucose is still unclear. More research is needed to understand fully how the circadian clock gene regulates the physiology of Sglt2's function and whether the circadian clock can provide additional benefits in controlling blood glucose. Here, we performed fasting and refeeding with Bmal1 knock out mice and their control mice. In vivo studies shown that fasting and refeeding regulation of renal expression of Sglt2 is complex and biphasic; Sglt2 mRNA levels decreased in response to fasting and were restored after refeeding, thus suggesting active transcriptional repression of Sglt2 in the fasting state. In molecular mechanism levels, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effects of Bmal1 and Rev-erbα on kidney Sglt2 expression and glucose reabsorption in mice. We demonstrated that Bmal1 plays an important role in the fasting-induced down regulation of proximal tubule Sglt2 expression and glucose reabsorption. Bmal1 increased the expression of Rev-erbα, and consequently repressed Nrf1, an enhancer of Sglt2 expression. Thus, this study identified Nrf1 as a clock-controlled gene that transmits information from Bmal1 and Rev-erbα to Sglt2. Our findings indicated that during fasting, glucagon induces Bmal1. Bmal1 then increases expression of Rev-erbα. Rev-erbα represses Nrf1, a key transcriptional enhancer of Sglt2, and diminishes glucose reabsorption in kidney proximal glomerular tubules. Under refed conditions, glucagon levels decrease, and the suppression of Nrf1 and Sglt2 is relieved. Furthermore, insulin further increases Nrf1 and Sglt2 through a yet-unidentified mechanism. In addition, under fasting conditions, glucagon-induced phosphorylation of MAPK is important in regulating glucose reabsorption via the Bmal1/Rev-erbα/Nrf1/Sglt2 pathway in RPTECs and in the kidneys. Our findings also suggested that insulin might potentially mitigate glucagon-mediated responses and independently upregulate Nrf1 and Sglt2. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery. The physiologic role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose. The kidney Bmal1/Nr1d1/Nrf1/Sglt2 axis identified herein may provide new molecular targets not only to ameliorate hyperglycemia in patients with diabetes but also to protect against environmental stresses such as shift work disorders. NIH R56HL137912 & R01HL169313 to XP, R01DK121490, R01HL137202, R01HL158054, R01HD094778, and VA Merit Award BX004113 to MMH, R01DK112042, R01DK134616, U54DK137307 to VV. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.