Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats.

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a nonobese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-wk old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with nondiabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed nonobese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.

Behavioral, metabolic, and renal outcomes of 1-month isolation in adolescent male Dahl salt-sensitive rats.

Social contact deficit is considered a stressful circumstance associated with various neural, hormonal, genetic, immune, and behavioral effects. A growing body of clinical and basic science evidence suggests that social isolation is linked to a higher risk of various neurological, cardiovascular, and metabolic diseases, including hypertension, diabetes mellitus, and obesity. However, the impact of the deficit of social interaction on kidney function is not well established. The Dahl salt-sensitive (SS) rat is a classical model of salt-induced hypertension and associated kidney injury. In this study, we investigated the effect of 30 days of social isolation (SI) on blood and urine electrolytes and metabolic, physiological, and behavioral parameters in adolescent male Dahl SS rats fed a normal 0.4% NaCl diet. SI rats demonstrated increased behavioral excitability compared with rats kept in groups. We also observed increased food consumption and a decrease in plasma leptin levels in the SI group without differences in water intake and weight gain compared with grouped animals. No changes in the level of blood and urine electrolytes, 24-h urine output, creatinine clearance, and albumin/creatinine ratio were identified between the SI and grouped rats. These findings indicate that 30 days of social isolation of adolescent Dahl SS rats affects metabolic parameters but has no apparent influence on kidney function.

Consequences of adolescent social isolation on behavior and synaptic plasticity in the dorsal and ventral hippocampus in male Wistar rats.

OBJECTIVE: Social interaction at a young age plays a critical role in the normal maturation of the brain and neuroendocrine system. Deprivation of social contacts has been associated with numerous cognitive and emotional abnormalities. However, neurobiological mechanisms that may underlie these effects remain poorly understood. In the present study, we examined the effect of 4-6-week social isolation during the adolescent period on rat spatial memory and emotional responses and investigated synaptic plasticity in the dorsal (DH) and ventral hippocampus (VH), which are known to be differently involved in these behaviors. METHODS: Male Wistar rats were housed individually or in groups of four for 4-6 weeks immediately after weaning. At the end of the isolation period, rats were subjected to behavioral testing or electrophysiological studies. Behavioral tests included behavioral excitability, sucrose preference, open field (OF), elevated plus maze (EPM), Morris water maze (MWM), and Y-maze test. For plasticity experiments, long-term potentiation (LTP) in Schaffer collateral/СA1 synapses was induced using high-frequency stimulation (HFS) on transverse hippocampal slices. RESULTS: Social isolation induced hyperexcitability, increased anxiety- and anhedonia-like behaviors, while no significant changes were observed in cognitive tasks. Electrophysiological recordings revealed enhanced short-term potentiation (STP) in the VH and suppressed LTP in the DH of isolated animals compared to group-housed controls. CONCLUSIONS: Our findings suggest that adolescent social isolation has distinct effects on synaptic plasticity in the VH and DH and leads to emotional dysregulation rather than impairments in cognitive performance.

Modulation of P2X4 receptor activity by ivermectin and 5-BDBD has no effect on the development of ARPKD in PCK rats.

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited pathology caused mainly by mutations of the polycystic kidney and hepatic disease 1 (PKHD1) gene, which usually leads to end-stage renal disease. Previous studies suggested that the P2X purinoreceptor 4 (P2X4 R) may play an important role in the progression of ARPKD. To test this hypothesis, we assessed the chronic effects of ivermectin (P2X4 R allosteric modulator) and 5-BDBD (P2X4 R antagonist) on the development of ARPKD in PCK/CrljCrl-Pkhd1pck/CRL (PCK) rats. Our data indicated that activation of ATP-mediated P2X4 R signaling with ivermectin for 6 weeks in high dose (50 mg/L; water supplementation) decreased the total body weight of PCK rats while the heart and kidney weight remained unaffected. Smaller doses of ivermectin (0.5 or 5 mg/L, 6 weeks) or the inhibition of P2X4 R signaling with 5-BDBD (18 mg/kg/day, food supplement for 8 weeks) showed no effect on electrolyte balance or the basic physiological parameters. Furthermore, cystic index analysis for kidneys and liver revealed no effect of smaller doses of ivermectin (0.5 or 5 mg/L) and 5-BDBD on the cyst development of PCK rats. We observed a slight increase in the cystic liver index on high ivermectin dose, possibly due to the cytotoxicity of the drug. In conclusion, this study revealed that pharmacological modulation of P2X4 R by ivermectin or 5-BDBD does not affect the development of ARPKD in PCK rats, which may provide insights for future studies on investigating the therapeutic potential of adenosine triphosphate (ATP)-P2 signaling in PKD diseases.

Knockout of the Circadian Clock Protein PER1 (Period1) Exacerbates Hypertension and Increases Kidney Injury in Dahl Salt-Sensitive Rats.

BACKGROUND: Circadian rhythms play an essential role in physiological function. The molecular clock that underlies circadian physiological function consists of a core group of transcription factors, including the protein PER1 (Period1). Studies in mice show that PER1 plays a role in the regulation of blood pressure and renal sodium handling; however, the results are dependent on the strain being studied. Using male Dahl salt-sensitive (SS) rats with global knockout of PER1 (SSPer1-/-), we aim to test the hypothesis that PER1 plays a key role in the regulation of salt-sensitive blood pressure. METHODS: The model was generated using CRISPR/Cas9 and was characterized using radiotelemetry and measures of renal function and circadian rhythm. RESULTS: SSPer1-/- rats had similar mean arterial pressure when fed a normal 0.4% NaCl diet but developed augmented hypertension after three weeks on a high-salt (4% NaCl) diet. Despite being maintained on a normal 12:12 light:dark cycle, SSPer1-/- rats exhibited desynchrony mean arterial pressure rhythms on a high-salt diet, as evidenced by increased variability in the time of peak mean arterial pressure. SSPer1-/- rats excrete less sodium after three weeks on the high-salt diet. Furthermore, SSPer1-/- rats exhibited decreased creatinine clearance, a measurement of renal function, as well as increased signs of kidney tissue damage. SSPer1-/- rats also exhibited higher plasma aldosterone levels. CONCLUSIONS: Altogether, our findings demonstrate that loss of PER1 in Dahl SS rats causes an array of deleterious effects, including exacerbation of the development of salt-sensitive hypertension and renal damage.

Characterization of purinergic receptor 2 signaling in podocytes from diabetic kidneys.

Growing evidence suggests that renal purinergic signaling undergoes significant remodeling during pathophysiological conditions such as diabetes. This study examined the renal P2 receptor profile and ATP-mediated calcium response from podocytes in glomeruli from kidneys with type 1 or type 2 diabetic kidney disease (DKD), using type 2 diabetic nephropathy (T2DN) rats and streptozotocin-injected Dahl salt-sensitive (type 1 diabetes) rats. A dramatic increase in the ATP-mediated intracellular calcium flux in podocytes was observed in both models. Pharmacological inhibition established that P2X4 and P2X7 are the major receptors contributing to the augmented ATP-mediated intracellular calcium signaling in diabetic podocytes. The transition in purinergic receptor composition from metabotropic to ionotropic may disrupt intracellular calcium homeostasis in podocytes resulting in their dysfunction and potentially further aggravating DKD progression.

Inhibition of protease-activated receptor 1 ameliorates behavioral deficits and restores hippocampal synaptic plasticity in a rat model of status epilepticus.

The blood-brain barrier (BBB) is a unique structure that controls substances exchange between the systemic circulation and the brain. Disruption of its integrity contributes to the development and progression of a variety of brain disorders including stroke, epilepsy and neurodegenerative diseases. It was shown that intracerebral thrombin level substantially increases following status epilepticus (SE). Inhibition of protease-activated receptor 1 (PAR1), the major thrombin receptor in the brain, produces an anti-epileptogenic and neuroprotective effects in an experimental model of temporal lobe epilepsy (TLE). Since serine proteases and PAR1 are implicated in the synaptic plasticity and memory formation, the aim of the present study was to elucidate the involvement of PAR1 in synaptic plasticity and behavior deficits following SE. Using lithium-pilocarpine model of TLE, we demonstrate that inhibition of PAR1 rescues SE-induced synaptic plasticity deficits in CA1 region of hippocampus. Although treatment with PAR1 antagonist does not ameliorate spatial learning deficits, it attenuates anxiolytic-like behavior in experimental rats after SE. Taken together; our data suggest an important role of PAR1 in SE-induced synaptic and behavioral alterations and provide a new insight into cellular mechanisms underlying behavioral impairments associated with epilepsy.