Growth Hormone and IGF1 Actions in Kidney Development and Function

Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD.

Therapeutic activity of sarpogrelate and dopamine D2 receptor agonists on cardiovascular and renal systems in rats with alloxan-induced diabetes

Background Dopamine D2 receptor agonists, bromocriptine and cabergoline, are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation was found between the initiation of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial activation of 5-hydroxytryptamine receptor 2 A (5-HT2A). The investigation aimed to examine the activity of sarpogrelate (a 5-HT2A receptor blocker) in reducing myocardial injury prompted by extended haul utilisation of D2 receptor agonists in rats with alloxan-induced diabetes. Methods Both bromocriptine and cabergoline were managed independently and combined with sarpogrelate for about a month in diabetic nephropathy rats. Both tail-cuff blood pressure and the BGL were recorded weekly. For all animals, the kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of lactate dehydrogenase-1 (LDH-1), cardiac troponin I, and tumor necrosis factor alpha 1 (TNF1). The triphenyltetrazolium chloride (TTC) staining method was used to determine the experimental myocardial infarction (MI) size. Results Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine and cabergoline, alone, or in combination with sarpogrelate fundamentally diminished the blood concentrations of alkaline phosphatase (ALP), Aspartate aminotransferase (AST), urea, and creatinine. Bromocriptine and cabergoline alone showed a noteworthy increase in the LDH-1, Troponin I, and TNF1 levels in the serum (p < 0.05). Paradoxically, utilising bromocriptine or cabergoline with sarpogrelate treatment altogether decreased the levels of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed through the TTC staining method. Conclusions The examination demonstrated that the combined use of sarpogrelate with bromocriptine or cabergoline decreased the potential adverse effects of these two drugs on the myocardial tissues.

Peroxisomal L-bifunctional protein (EHHADH) deficiency causes male-specific kidney hypertrophy and proximal tubular injury in mice

Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. Methods: We studied kidneys of WT and Ehhadh KO mice on a C57BL/6N background using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, and metabolomics. To assess the role of androgens in the kidney phenotype of Ehhadh KO mice, mice underwent orchiectomy. Results: We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipid levels. Orchiectomy of Ehhadh KO mice decreased the number of KIM-1 positive cells to WT levels. We revealed a pronounced sexual dimorphism in the expression of peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. Conclusions: Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.

Deficiency of peroxisomal L-bifunctional protein (EHHADH) causes male-specific kidney hypertrophy and proximal tubular injury in mice

Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. Methods: We studied kidneys of WT and Ehhadh KO mice using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, metabolomics and orchiectomy. Results: We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipids levels. Orchiectomy of Ehhadh KO mice reversed kidney enlargement and decreased the number of KIM-1 positive cells. We reveal a pronounced sexual dimorphism in the expression peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. Conclusions: Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.

Therapeutic activity of sarpogrelate, and dopamine D2 receptor agonists on cardiovascular and renal systems in alloxan-induced diabetic rats

Background: The investigation aims to represent the activity of sarpogrelate, a particular 5-HT (2A) receptor blocker, in reducing myocardial injury prompted by extended haul utilization of D2 agonist drugs in diabetic rats. Dopamine D2 agonists are notable medications in the treatment of Parkinsonism, hyperprolactinemia, and hyperglycemia. An affiliation showed between the enlistment of myocardial injury ailment and long term treatment with dopamine D2 agonist drugs identified with the partial initiation of 5-HT 2a receptors. Methods: Both bromocriptine and cabergoline were managed independently and combined with sarpogelate for about a month to diabetic nephropathy rats. Both tail-cuff blood pressure and BGL were recorded weekly. For all animals, kidney hypertrophy index, serum creatinine, blood urea nitrogen, alanine transaminase, and aspartate transaminase levels were measured after one month of treatment. The severity of the cardiac injury was assessed by the estimation of LDH-1, cardiac troponin I, and TNFα. Triphenyl tetrazolium chloride staining method used to determine experimental myocardial infarction (MI) size. Results: Bromocriptine and cabergoline created a significant reduction in BGL, BP, and kidney hypertrophy index in diabetic nephropathy rats. Administration of bromocriptine, cabergoline, alone, or in combination with sarbogrelate fundamentally diminished blood concentrations of ALP, AST, urea, and creatinine. Bromocriptine and cabergoline alone showed noteworthy ascending of LDH-1, Troponin I, and TNFα1 levels in the serum (p<0.05). Paradoxically, utilizing bromocriptine and cabergoline with sarpogrelate treatment altogether diminished the degree of the myocardial biomarkers in the serum. A mix of bromocriptine or cabergoline with sarpogrelate diminished the level of the myocardial infarct size in the heart assessed utilizing the TTC staining method. Conclusions: The examination exhibited that both bromocriptine and cabergoline could be utilized safely in blend with sarpogrelate for a long duration of treatment for diseases like hypertension and diabetes.

MON-692 Effect of High Salt Diet on Kidney Weight in Neonatal Streptozotocin Induced Noninsulin Dependent Diabetic Rats

Diabetic kidney hypertrophy may contribute to the development of diabetic kidney disease. Hyperglycemia is recognized as a cause for the kidney endangerment. Salt may accelerate progression of kidney disease in diabetes. To further study the effect of high salt intake on kidney disease we used neonatal streptozotocin induced Noninsulin Dependent Diabetic (NIDD) rats fed ad libitum with regular Purina chow and 2% salt Purina chow. Rats in 5 groups were sacrificed at 6 weeks. Each group had 5–7 rats of diabetics on 2% salt and on regular chow and controls on 2% salt and on regular chow. Blood glucose in diabetics on salt ranged between 185±19–576±20 and in diabetics on regular chow 184±20–458±78 mg/dl. Controls on 2% salt 105±8.6–133±10.3 and controls on regular chow 110±8.9 - 130±3.11. Kidney weights in diabetics on salt was 1.85±0.09–2.0±0.06 gr, diabetics on regular chow 1.6±0.04 - 1.56±0.06 controls on salt 1.19±0.03–1.32±0.05 and controls on regular chow 1.23±0.03. Blood glucose in diabetics on salt and on regular chow was higher than in controls p˂0.05 but did not differ between the diabetic groups. Kidney weight was increased in both diabetic groups compared with controls p˂0.05 and was increased in diabetics on salt compared with diabetics on regular chow p˂0.05 at all glucose levels. Controls on salt and on regular chow had similar kidney weights. Also kidney weight relative to body weight was higher in diabetics than in controls p˂0.05 and was higher in diabetics on salt compared to diabetics on regular chow p˂0.05, but there was no difference between controls on salt and controls on regular diet. Kidney % of water was similar in all four groups but protein to kidney DNA ratio was higher in the diabetic groups p˂0.05 confirming the kidney hypertrophy. Insulin sensitivity measured in controls was not different between groups when glucose transport, glucose oxidation and lipogenesis were measured in fat cells showing no effect of salt on insulin sensitivity. We suggest that high salt intake is an additional risk factor for increased kidney weight in NIDDM that is additive to that of the prevailing glycemia.