ABSTRACT Aim Chronic glucocorticoid (GC) therapy induces severe metabolic complications, notably secondary sarcopenia driven by excessive glucocorticoid receptor (GR)‐mediated catabolism. Although sex steroids protect skeletal muscle metabolism, the role of sex hormone‐binding globulin (SHBG), the primary determinant of sex steroid bioavailability, in modulating local endocrine crosstalk under GC stress remains unknown. Methods We evaluated the clinical correlation between serum SHBG and endocrine factors in a rheumatology cohort frequently exposed to GC. To establish causality and underlying mechanisms, male and female human SHBG‐transgenic ( hSHBG ‐Tg) mice, with or without gonadectomy, and C2C12 myoblasts were challenged with dexamethasone (DXM) to simulate GC‐induced muscle atrophy. Results In patients with high cumulative GC exposure (≥ 10,000 mg), circulating SHBG strongly inversely correlated with serum myostatin ( r = −0.7153, p = 0.0076). In mice, hSHBG ‐Tg significantly rescued DXM‐induced loss of muscle mass (quadriceps, gastrocnemius, tibialis anterior) and grip strength in females; notably, this protection was entirely abolished by ovariectomy. Mechanistically, hSHBG ‐Tg blunted GR Ser211 phosphorylation and downregulated the ubiquitin ligases Fbxo32 and Trim63 , while preserving estrogen receptor (ER) target genes ( Tff1 and Pgr ). In vitro, estradiol antagonized DXM‐induced Trim63 transcription via ER, and co‐treatment with SHBG sustained this anti‐catabolic effect by extending estradiol bioavailability. Conclusions SHBG acts as a promoter of estrogen bioavailability that coordinates a protective endocrine crosstalk, counteracting GR‐driven catabolism in female skeletal muscle. These findings identify SHBG as a key metabolic determinant and a promising therapeutic target to prevent corticosteroid‐induced muscle wasting.
ABSTRACT Hypertension involves an impairment of renal sodium excretion along with activation of pro‐inflammatory responses in the kidney. Dendritic cells (DCs) are professional antigen‐presenting cells that sense disturbances in cell and tissue homeostasis to orchestrate T cell activation and recruitment. Renal DCs distribute as a cellular network throughout the renal interstitium, forming an interface between innate and adaptive immunity. Here, we explore what is known about renal cross‐talk following prohypertensive stimuli, which modify renal DCs, T cell polarization, and renal function, leading to hypertension. We also present the phenotypic and functional heterogeneity of DCs, including literature on in vitro and in vivo signaling mechanisms in a variety of hypertensive models. Current studies indicate that renal sodium retention caused by prohypertensive stimuli requires DC function. The prohypertensive action of DCs also requires T cell function. Several cross‐talk mechanisms have been proposed, such as signals from the kidney to the DC, including salt activation of DC's via RAAS receptor signaling, and DC‐dependent recruitment of T cells to the kidney then promoting increased renal tubular sodium reabsorption. Knowledge gaps include specific functions of renal DC subtypes, sex differences in DC‐mediated hypertension, and clinical studies on DC function in hypertension. The identification of mechanisms leading to renal DCs activation in hypertension may offer new strategies for the prevention and treatment of hypertension.
