Alteration in renal function has long been known to be a consequence of liver disease. However, the mechanisms by which the liver can regulate kidney function under basal conditions and in response to liver disease have yet to be fully understood. The liver is a complex organ capable of producing metabolites, including ketones, bile acids, and hepatokines such as fibroblast growth factor 21. Alterations in the hepatic production of these metabolites and hormones can significantly affect renal function and may play a crucial role in the development of kidney disease. The goal of this review is to summarize the mechanisms by which liver-derived metabolites and hepatokines regulate kidney function in health and disease.

Chronic d-galactose (d-gal) treatment is a model to induce accelerated aging-like phenotypes in rodents. However, the sex differences in behavioral and musculoskeletal manifestations of this model are not well understood. Heme oxygenase-1 (HO-1) is a cytoprotective protein that may have anti-aging properties. The goal of this study was to better understand the sex differences in the behavioral and musculoskeletal effects of chronic d-gal treatment in C57BL/6J mice, as well as the role of HO-1 induction or inhibition. Eight-week-old male and female mice received daily saline or d-gal injections (500 mg/kg, s.c.) for 12 weeks. After this time, mice in the d-gal group were randomized into three groups (n = 6/group/sex): d-gal, d-gal + cobalt protoporphyrin (CoPP) (5 mg/kg, s.c. weekly), and d-gal + zinc deutroporphyrin bisglycol (ZnBG) (42 mg/kg, i.p. triweekly) for a period of 4 weeks. Open-field, novel-object recognition, Barnes maze, grip strength, micro-computed tomography (µ-CT), histology, and protein analysis were performed. Chronic d-gal treatment resulted in a sexual dimorphic response, with female mice being more prone to develop deficits in both short- and long-term spatial memory as well as in non-spatial memory. Male mice exhibited deficits only in long-term spatial memory when treated chronically with d-gal. Inhibition of HO-1 was protective in both females and males. Chronic d-gal treatment did not accelerate the development of osteoporosis or sarcopenia in either males or females. Our results demonstrate a sexual dimorphic response to the chronic effects of d-gal treatment on aging, with greater effects in females than in males, which is dependent on HO-1.

Chronic d-galactose (d-gal) injection is an experimental model of accelerated aging in rodents. However, the cardiovascular phenotypes of this model have been poorly characterized, especially as they relate to sex differences. The goal of this study was to investigate the cardiovascular effects of chronic d-gal injection in male and female C57BL/6 mice and the impact of HO-1 induction or inhibition in this model. Forty-eight 8-week-old male and female C57BL/6 mice were divided randomly into four groups ( n = 6): control, d-gal, d-gal + CoPP, and d-gal + ZnBG. Body weight, echocardiography, blood pressure measurement, Doppler ultrasound, echoMRI, micro-CT, histopathology, and protein analysis were performed. Our results show a strong sexual dimorphism in the cardiovascular effects of d-gal treatment and the effects of HO-1 induction or inhibition. Male mice were found to be more prone to systolic dysfunction and oxidative stress upon d-gal treatment and benefited more from the protective effects of HO-1 induction. Female mice were found to be protected from the cardiac effects of d-gal treatment yet were more prone to the effects of HO-1 inhibition. Our results demonstrate a sexually dimorphic response to the cardiovascular effects of d-gal treatment and alterations in HO-1. Graphical Abstract

Background: Women with gestational diabetes mellitus (GDM), a condition of pregnancy-induced hyperglycemia, are more likely to develop cardiovascular disease (CVD) within 3 to 10 years following pregnancy. One reason for the lack of progress into the cardiovascular complications of GDM is the need for appropriate preclinical models that mimic human GDM. We have previously used the insulin receptor antagonist (S961) to develop a novel hormonal mouse model of reversible GDM. Hypothesis: We hypothesized that S961-induced GDM mice will exhibit CVDs later in life. Aim: To determine the mechanisms underlying CVD in hormonal model of GDM. Methods: Sixteen (16) week-old C57BL/6J female mice were treated with S961 or saline (n=4) from the second trimester of pregnancy until delivery to develop hormonal mouse model of GDM. Animals were followed up to 10 weeks after gestation. Blood glucose levels were measured with a glucometer. Fasting insulin, circulating endothelin-1 (ET-1) and nitrite were measured by colorimetry. Cardiac structure and function were measured by high resolution ultrasound echocardiography (VEVO 3100) and pulse wave velocity was measured by Pulse Wave Doppler (Indus instrument). Exercise tolerance test was performed on treadmill (Columbus Instrument). Aortic sirtuin-1 (SIRT-1) and ETA receptor were determined by western blot. Vascular reactivity was determined by wire myograph (DMT). Aortic fibrosis and calcification were determined by picrosirius red and Von Kossa staining. Data were analyzed by unpaired t- tests and results are expressed as mean ± standard error of mean. Results: S961-induced GDM mice exhibit hyperglycemia (169.5 ± 3.6 vs. 105.5 ± 10.8mg/dL, p<0.004 ) and hyperinsulinemia (1.9 ± 0.2 vs. 0.8 ± 0.1ng/ml , p<0.01 ) which mimics the condition observed in human GDM. Interestingly, S961-induced GDM mice went on to develop systolic and diastolic dysfunction, vascular stiffness (3.7 ± 0.1 vs. 3.1 ± 0.08 m/s, p <0.005 ), exercise intolerance and increased thickness of the cardiac wall at 10 weeks post-delivery. Plasma ET-1 was elevated in our model during pregnancy (28.1 ± 1.7 vs. 5.2 ± 0.2pg/ml, p <0.002 ) and at 10 weeks post-delivery (19.9 ± 2.9 vs. 6.7 ± 0.7pg/ml, p <0.05 ). Circulating NO and aortic expression of SIRT-1, that is involved in endothelial longevity by regulating endothelial NO synthase, is reduced in GDM mice. Vascular relaxation to acetylcholine was impaired in S961-induced GDM compared to control. Additionally, GDM mice exhibited increased arterial wall thickness, collagen accumulation, and calcium deposits in the wall of aorta. Conclusion: Insulin receptor antagonist (S961)-treated mice develop GDM similar to that observed in pregnant women. Moreover, S961 treated mice develop cardiac dysfunction and vascular stiffness at 10 weeks post-delivery. Alterations in ET-1, SIRT-1, NO levels, aortic fibrosis and calcification may be responsible for the development of CVD in this model. Funding: NIH-NIDDK (1R01DK121748-01A1), AHA Postdoctoral Award (23POST1020493), NIH-COBRE Pilot Grant (SP15081) and NIGMS (P20GM104357 & P30GM149404 ). 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.

Mechanisms underlying the future development of CVD in mothers with GDM were investigated using a mouse model of GDM that mimics the condition observed in human GDM. Examining the aorta in the later life of the GDM model reveals increased arterial stiffness and endothelin activation associated with vascular remodeling. In addition, kinome analysis reveals suppressed cardiac NO/cGMP/PRKG and impaired AMPK-SIRT1 signaling pathways, which corroborate the impaired ventricular relaxation observed in later life in GDM mothers.