Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 18  |  Issue : 5  |  Page : 803-808

The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats


1 Department of Emergency Surgery, The Daqing Oilfield General Hospital, Daqing, China
2 Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, China
3 Department of Emergency Surgery, The Fourth Hospital of Jilin University, Changchun, China
4 Department of Pharmacology, Daqing Campus of Harbin Medical University, Daqing, China
5 Department of Urologic Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, China
6 The Hepatosplenic Surgery Center, Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
7 School of Nursing, Daqing Campus of Harbin Medical University, Daqing, China

Date of Submission21-Sep-2014
Date of Decision02-Dec-2014
Date of Acceptance14-Apr-2015
Date of Web Publication18-Sep-2015

Correspondence Address:
Lin-Lin Zhang
School of Nursing, Daqing Campus of Harbin Medical University, Daqing
China
Tie-Hui Zhang
Department of Urologic Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.160885

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  Abstract 

Male infertility caused by testicular damage is one of the complications of diabetes mellitus. The calcium-sensing receptor (CaSR) is expressed in testicular tissues and plays a pivotal role in calcium homeostasis by activating cellular signaling pathways, but its role in testicular damage induced by diabetes remains unclear. A diabetic model was established by a single intraperitoneal injection of streptozotocin (STZ, 40 mg kg−1 ) in Wistar rats. Animals then received GdCl 3 (an agonist of CaSR, 8.67 mg kg−1 ), NPS-2390 (an antagonist of CaSR, 0.20 g kg−1 ), or a combination of both 2 months after STZ injection. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy rats, indicating testicular damage and dysfunction in STZ-induced diabetic rats. Compared with healthy controls, the testicular tissues of diabetic rats overexpressed the CaSR protein and had higher levels of malondialdehyde (MDA), lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and higher numbers of apoptotic germ cells. The testicular tissues from diabetic rats also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3 in addition to higher phosphorylation rates of c-Jun NH 2 -terminal protein kinase (JNK), p38, and extracellular signaling-regulated kinase (ERK) 1/2. The above parameters could be further increased or aggravated by the administration of GdCl 3 , but could be attenuated by injection of NPS-2390. In conclusion, the present results indicate that CaSR activation participates in diabetes-induced testicular damage, implying CaSR may be a potential target for protective strategies against diabetes-induced testicular damage and could help to prevent infertility in diabetic men.

Keywords: apoptosis; calcium-sensing receptor; diabetes; testicular damage


How to cite this article:
Kong WY, Tong LQ, Zhang HJ, Cao YG, Wang GC, Zhu JZ, Zhang F, Sun XY, Zhang TH, Zhang LL. The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats. Asian J Androl 2016;18:803-8

How to cite this URL:
Kong WY, Tong LQ, Zhang HJ, Cao YG, Wang GC, Zhu JZ, Zhang F, Sun XY, Zhang TH, Zhang LL. The calcium-sensing receptor participates in testicular damage in streptozotocin-induced diabetic rats. Asian J Androl [serial online] 2016 [cited 2021 Aug 2];18:803-8. Available from: https://www.ajandrology.com/text.asp?2016/18/5/803/160885 - DOI: 10.4103/1008-682X.160885


  Introduction Top


Diabetes mellitus is a prominent public health problem and is rapidly increasing in prevalence worldwide. [1] Although the adverse effects of diabetes on male fertility have long been controversial, it is now accepted that diabetes can cause testicular damage by inducing various subtle molecular changes that are important for sperm quality and function; thus, diabetes is considered to be one of the causes of male infertility. [2],[3] However, the mechanism underlying the diabetes-induced testicular damage remains unclear. Oxidative stress and apoptosis of germ cells are two major events involved in testicular damage induced by diabetes, [4],[5] and calcium homeostasis contributes to these mechanisms. [6]

The calcium-sensing receptor (CaSR), a member of the G-protein coupled receptors family, plays a pivotal role in disorders of calcium homeostasis by activating many signaling pathways. [7] Pancreatic insulin secreting β-cells express extracellular CaSR, and the activation of CaSR leads to a transient increase in insulin secretion followed by the inhibition of basal and nutrient-stimulated insulin secretion at supra-physiological levels of Ca 2+ . [8] L-histidine-induced CaSR activation inhibits glucose-induced insulin secretion in β-cells through spatial rearrangement of the CaSR and L-type voltage-dependent calcium channels [9] indicating that CaSR may participate in the pathogenesis of diabetes.

CaSR has been found in the parathyroid, [10] heart, [11] kidney, [12] and bone. [13] Functional CaSR has also been found to be expressed in testicular tissues and sperm cells, which can be activated by calcimimetics. Localization of CaSR is an important contributor to the regulation of cell proliferation and apoptosis. [14] It was recently reported that CaSR activation plays a critical role in the apoptosis of cardiomyocytes in diabetes-induced cardiac injury in rats by inducing calcium overload and subsequent activation of mitochondrial and mitogen-activated protein kinase (MAPK) pathways. [11] Therefore, we conducted the present study to investigate whether CaSR activation participates in diabetes-induced testicular damage using experimental streptozotocin-induced diabetic rats.


  Materials and Methods Top


Experimental animals

Fifty-eight male Wistar rats weighing between 200 and 220 g were supplied by the Experimental Animal Center of Harbin Medical University, China. The animals were given free access to rodent chow and water under humane care and were housed in special polycarbonate cages in a controlled environment (22-24°C, 55%-70% humidity, 12 h light/12 h dark cycle). All experimental protocols were performed in accordance with the guidelines of the Experimental Animal Ethic Committee of Harbin Medical University, China (Animal Experimental Ethical Inspection Protocol No. 2009104).

Antibodies and reagents

The antibodies (Abs) against CaSR, extracellular signaling-regulated kinase (ERK), JNK, and p38 were obtained from Cell Signaling Technology (Shanghai, China). The Abs against caspase-3, Bcl-2, Bax, and GAPDH were from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Gadolinium (III) chloride (GdCl 3 , an agonist of CaSR), STZ, and NPS-2390 (an antagonist of CaSR) were from Sigma-Aldrich (Beijing, China).

Animal experiments

Forty rats were given a single intraperitoneal injection of 40 mg kg−1 STZ which was dissolved in fresh citrate buffer (pH 4.5) at a concentration of 0.1 mol l−1 . The fasting blood glucose levels were monitored by a blood glucose analyzer (OneTouch Ultra, Johnson and Johnson, China) 3 days after STZ injection. Thirty rats with blood glucose levels no <16.7 mmol l−1 measured three consecutive times were considered diabetic. We used 30 diabetic rats and 18 healthy rats in the study.

Two months after STZ injection, six diabetic rats, and six healthy rats were euthanized, bilateral testes were removed and weighed, and the sera was harvested as described below. The remaining diabetic rats were randomly assigned into four groups (n = 6): untreated, GdCl 3 , NPS-2390, and GdCl 3 + NPS-2390. The diabetic rats in the untreated group received daily intraperitoneal injections of 1 ml of citrate buffer. GdCl 3 or NPS-2390 was intraperitoneally injected daily at a dose of 8.67 mg kg−1 or 0.20 g kg−1 , in the GdCl 3 or NPS-2390 groups, respectively. In the GdCl 3 + NPS-2390 group, NPS-2390 was given 2 h prior to the GdCl 3 injection. Two groups (n = 6) of healthy rats were given daily intraperitoneal injections of either 1 ml of citrate buffer or GdCl 3 at a dose of 8.67 mg kg−1 . One week later, rats were euthanized by intraperitoneal injection of an overdose of pentobarbital sodium (60 mg kg−1 ). Blood samples were collected from the vena cava, and sera were harvested and kept at − 80°C. Bilateral testes were removed rapidly, weighed, and then frozen and stored in liquid nitrogen.

Measurement of serum testosterone

Serum levels of testosterone were measured using a testosterone ELISA Kit (ab108666) provided by Abcam Trading Co., Ltd., (Shanghai, China) according to the manufacturer's instruction.

Measurements of MDA, SOD, and GSH-Px in testicular tissues

The level of malondialdehyde (MDA) and the enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured using commercial kits from Nanjing Jiancheng Bioengineering Institute, China. Briefly, testicular tissues were weighed and homogenized in ice-cold phosphate buffered saline. The protein content of testicular homogenates was measured using a Coomassie Protein Assay Kit (Bioworld Technology, Inc., Nanjing, China). The level of MDA was estimated by evaluating the thiobarbituric acid (TBA) reacting substances at the wavelength of 532 nm. The activity of SOD was quantified as the rate of inhibition of nucleotide oxidation at a wavelength of 412 nm. The activity of GSH was determined by the ratio of the reduced glutathione to the oxidized glutathione at a wavelength of 550 nm. The results for MDA, SOD, and GSH-Px were defined as nmol mg−1 protein, U mg−1 protein, and U mg−1 protein, respectively. The experiments were repeated 3 times.

Measurement of apoptotic germ cells in the testes

Testicular sections (5 μm) were prepared and stained with the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) (Roche, Shanghai, China). The nuclei were counterstained by hematoxylin. The stained sections were examined by light microscopy. The nuclei of TUNEL-positive apoptotic germ cells were stained brown, and the nuclei of normal germ cells were blue. The TUNEL-positive germ cells were counted in a double-blind manner and 10 seminiferous tubule cross-sections per slide were randomly selected. The apoptosis index was calculated by dividing the numbers of positive staining nuclei by the total number of nuclei in the cells.

Western blot analysis

Testicular tissues were homogenized in protein lysate buffer, and total protein was evaluated as above. Homogenates were resolved on polyacrylamide SDS gels and electrophoretically transferred to polyvinylidene difluoride membranes. The membranes were blocked with 5% nonfat dried milk for 2 h, incubated overnight at 4°C with primary Abs, and then subsequently incubated with alkaline phosphatase-conjugated secondary Abs. They were developed by 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium (Tiangen Biotech Co., Ltd., Beijing, China). The blots were measured by the gray analysis with Quantity One software (Bio-Rad Laboratories, Shanghai, China).

Statistical analysis

All data were presented as the mean ± standard error of mean (s.e.m.). Comparisons were performed with a one-way analysis of variance followed by Student-Newman-Keuls test using an SPSS (Statistical Package for the Social Sciences) 18.0 software (IBM Corporation, NY, USA). P < 0.05 was considered to be statistically significant.


  Results Top


Damaged testicular tissues express higher levels of the calcium-sensing receptor in diabetic rats

Diabetic rats had significantly lower body weights ([Figure 1]a) and testicular weights ([Figure 1]b) 2 months after STZ injection compared to healthy rats. Serum levels of glucose were significantly higher in diabetic rats compared to healthy rats ([Figure 1]c), but serum levels of testosterone were significantly lower in diabetic rats compared to healthy rats ([Figure 1]d). The above results indicate that STZ-induced diabetes was successfully established in rats as evidenced by testicular damage and dysfunction. We next demonstrated that the level of CaSR protein expression was significantly higher in testicular tissues from diabetic rats compared to healthy rats ([Figure 1]e), indicating that CaSR may participate in the testicular damage in STZ-induced diabetic rats.
Figure 1: Body and testicular weights, serum levels of glucose and testosterone, and testicular expression of the calcium-sensing receptor. Diabetic rats were fasted, weighed, (a) and killed 2 months after streptozotocin injection. The bilateral testes of each rat were removed and weighed (b). Blood samples were collected to harvest sera, which were used to measure the levels of glucose (c) and testosterone (d). (e) Testicular tissues were subjected to Western blot to detect the expression of the calcium-sensing receptor (CaSR). The density of each band was normalized to that of GAPDH. Untreated healthy rats served as controls. Results are expressed as the mean ± s.e.m. (n = 6). "**" (P < 0.001) versus healthy controls.

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CaSR affects lipid peroxidation and antioxidant activity in testicular tissues

We investigated whether the activity of CaSR was associated with the level of MDA and the activities of SOD and GSH-Px, which are key factors involved in testicular damage induced by STZ in diabetic rats. [15] As shown in [Figure 2]a-c, the level of MDA ([Figure 2]a) was significantly higher in testicular tissues of diabetic rats than that of healthy rats, while the testicular activities of SOD ([Figure 2]b) and GSH-Px ([Figure 2]c) were significantly lower in diabetic rats compared to healthy rats. Administration of GdCl 3 , an agonist of CaSR, further increased the level of MDA and reduced the activities of SOD and GSH-Px. However, injection of NPS-2390, an antagonist of CaSR, reduced the level of MDA and increased the activities of SOD and GSH-Px. Furthermore, NPS-2390 also attenuated the alterations of MDA, SOD, and GSH-Px induced by GdCl 3 in diabetic rats ([Figure 2]). Administration of GdCl3 also increased the level of MDA and reduced the activities of SOD and GSH-Px in healthy rats ([Figure 2]).
Figure 2: Lipid peroxidation and antioxidant activity in testicular tissues. Diabetic and healthy rats, as shown in Figure 1 , were injected with vehicle (citrate buffer), GdCl3, GdCl3 + NPS-2390 or NPS-2390 for 1 week and then killed to collect the testicular tissues. The levels of MDA (a) and the activities of SOD (b) and GSH-Px (c) were measured. Results are expressed as the mean ± s.e.m. (n = 6). "*" (P < 0.05) and "**" (P < 0.001) versus untreated healthy rats; "φ" (P < 0.05) and "φ φ" (P < 0.001) versus GdCl3-treated diabetic rats. "#" (P < 0.05) and "##" (P < 0.001) indicate a significant increase, and "†" (P < 0.05) indicates a significant reduction from untreated diabetic rats.

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CaSR affects germ cell apoptosis in testicular tissues

Injection of STZ led to the apoptosis of germ cells in diabetic rats, thus contributing to the testicular dysfunction. [15] Here, we demonstrated that there were more apoptotic germ cells in testicular tissues from diabetic rats compared to healthy controls ( [Figure 3]a and b). Administration of GdCl 3 further increased the apoptotic index, while injection of NPS-2390 reduced the apoptotic index and also attenuated the increased apoptotic index induced by GdCl 3 in diabetic rats ([Figure 3]b-g). Administration of GdCl3 increased the apoptotic index in healthy rats ([Figure 3]a, f, and g).
Figure 3: Apoptosis of germ cells in testicular tissues. (a-f) Representative testicular sections stained by TUNEL (×400 magnifications). Healthy (a) and diabetic (b) rats were injected with vehicle while diabetic rats were injected with GdCl3 (c), GdCl3 + NPS-2390 (d) or NPS-2390 (e) for 1 week, healthy rats were injected with GdCl3 (f) for 1 week, and then all animals were killed to collect testicular tissues. (g) TUNEL-positive germ cells were counted to record the apoptosis index. Results are expressed as the mean ± s.e.m. (n = 6). "*" (P < 0.05) and "**" (P < 0.001) versus untreated healthy rats; "φ" (P < 0.05) and "φφ" (P < 0.001) versus GdCl3-treated diabetic rats. "#" (P < 0.05) and "##" (P < 0.001) indicate a significant increase, and "†" (P < 0.05) indicates a significant reduction from untreated diabetic rats.

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CaSR affects the expression of Bcl-2, Bax, and caspase-3 proteins in testicular tissues of diabetic rats

We further investigated the alteration of apoptosis-related proteins by Western blotting analysis of testicular homogenates with Abs against rat Bcl-2, Bax, and cleaved caspase-3. The expression of Bcl-2 was downregulated in testicular tissues from diabetic rats compared to healthy controls ([Figure 4]a). The expression of Bax ([Figure 4]b) and cleaved caspase-3 ([Figure 4]c) was upregulated in testicular tissues from diabetic rats compared to healthy controls. Administration of GdCl3 further reduced the expression of Bcl-2 ([Figure 4]a) and increased the expression of Bax ([Figure 4]b) and cleaved caspase-3 ([Figure 4]c) in testicular tissues from diabetic rats. However, simultaneous injection of NPS-2390 attenuated the alterations in Bcl-2, Bax, and cleaved caspase-3 expression induced by GdCl3 in diabetic rats ([Figure 4]a-4c).
Figure 4: Expression of Bcl-2, Bax, and caspase-3 proteins in testicular tissues. Western blot analysis was used to detect the expression of Bcl-2 (a) Bax, (b) and cleaved caspase-3 (c) proteins in testicular homogenates from healthy rats injected with vehicle (lane 1), diabetic rats injected with vehicle (lane 2), and GdCl3 (lane 3) or GdCl3 + NPS-2390 (lane 4) for 1 week. The density of each band was measured and compared to that of GAPDH. Results are expressed as the mean ± s.e.m. (n = 6). "*" (P < 0.05) and "**" (P < 0.001) versus untreated healthy rats; "#" (P < 0.05) and "##" (P < 0.001) versus untreated diabetic rats; and "ƒÓ" (P < 0.05) and "ƒÓƒÓ" (P < 0.001) versus GdCl3-treated diabetic rats.

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CaSR affects the phosphorylation of JNK, p38, and ERK proteins in testicular tissues of diabetic rats

c-Jun NH 2 -terminal protein kinase (JNK), p38, and extracellular signal-regulated protein kinase (ERK) act as vital regulators of cell apoptosis and proliferation signaling pathways. [16],[17] Therefore, we investigated the phosphorylation of these proteins by Western blotting analysis. The phosphorylation rates of JNK ([Figure 5]a), p38 ([Figure 5]b) and ERK ([Figure 5]c) were all significantly increased in testicular tissues from diabetic rats compared to healthy controls. Administration of GdCl3 further increased their phosphorylation, while simultaneous injection of NPS-2390 attenuated the increased phosphorylation of these proteins induced by GdCl3 in diabetic rats ([Figure 5]a-c).
Figure 5: Phosphorylation of JNK, p38, and ERK proteins in testicular tissues. Western blot analysis was used to detect the expression of phosphorylated JNK (P-JNK) and total JNK (T-JNK) (a), phosphorylated p38 (P-p38) and total p38 (T-p38) (b), and phosphorylated ERK (P-ERK) and total ERK (T-ERK) (c). The testicular homogenates were taken from healthy rats injected with vehicle (lane 1), diabetic rats injected with vehicle (lane 2), and GdCl3 (lane 3) or GdCl3 + NPS-2390 (lane 4) for 1 week. The density of each band of P-JNK, P-p38 or p-ERK was normalized to the respective total form of the protein. Results are expressed as the mean ± s.e.m. (n = 6). "*" (P < 0.05) and "**" (P < 0.001) versus untreated healthy rats; "#" (P < 0.05) and "##" (P < 0.001) versus untreated diabetic rats; and "ƒÓ" (P < 0.05) versus GdCl3-treated diabetic rats.

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  Discussion Top


STZ is a well-known genotoxic agent and a potential source of oxidative stress that has been widely used to induce diabetes in experimental animals by causing damage or dysfunction in pancreatic insulin secreting β-cells. [18] The number of germ cells and the ratio of germ cells/supporting cells are both reduced in the testes of diabetic rats. [19] Oxidative stress, DNA damage, and mitochondrial dysfunction are involved in the damage to reproductive tissues in streptozotocin-induced diabetes. [4],[5],[20],[21],[22],[22] Accordingly, the present study has demonstrated that testicular tissues from STZ-injected rats had higher MDA content and lower SOD and GSH-Px activity. MDA is a product of lipid peroxidation and is used to measure the damage caused by free radicals in diabetic rats. [23] SOD and GSH-Px have antioxidant properties against oxidative stress that help maintain the viable reproductive ability and protect testicular tissues from the damage caused by reactive oxygen species. [24] Several antioxidants have been used to prevent testicular damage in diabetic animals. [25],[26]

Following the cloning and characterization of CaSR as an extracellular Ca 2+ -sensing receptor in 1993, [10] it has become clear that CaSR has immense functional versatility by activating several different signaling pathways. CaSR plays crucial roles in both calcium homeostasis and calcium-independent disorders including diabetes and infertility. [14],[27] CaSR agonists, antagonists, and other drugs mediated through CaSR have been used in the management of many disorders. [7] For the first time, the present study demonstrated that CaSR was upregulated in testicular tissues in diabetic rats and its activation is closely associated with testicular damage. Specific activation of CaSR by GdCl 3 aggravated, and specific inhibition of CaSR by NPS-2390 attenuated, testicular damage caused by STZ-induced diabetes as evidenced by alterations of in oxidative markers, apoptosis of germ cells, and activation of the mitochondrial apoptotic pathways.

It is known that diabetes causes testicular dysfunction by inducing the apoptotic death of germ cells. [27] Here, we could also show that STZ-induced apoptosis of germ cells by activating the mitochondrial pathway in accordance with previous reports. [18],[20],[28] The mitochondrial pathway is a classic apoptotic pathway during which the permeability of the outer mitochondrial membrane increases resulting in the opening of the permeability transition pore [29] causing the release of apoptogenic molecules from the intermembrane space into the cytoplasm. [29],[30] The opening of the permeability transition pore is regulated by Bcl-2 family members, [31] which consist of antiapoptotic proteins like Bcl-2 and pro-apoptotic proteins like Bax. [32],[33] The main function of Bcl-2 is to stabilize mitochondrial membrane potential and inhibit Cyt-c release and caspase activation, while Bax plays a role that opposes Bcl-2. [34],[35] The present study showed that activation of CaSR reduced Bcl-2 expression and increased Bax expression accompanied by upregulation of cleaved caspase-3, indicating that CaSR plays a proapoptotic function in the apoptotic death of germ cells in diabetic rats.

The MAPK pathway is involved in maintaining normal spermatogenesis. [36] ERK, JNK, and p38-MAPK, key members of the MAPK superfamily, play major roles in cell apoptosis and survival. [16] The JNK-p38-MAPK pathway is closely associated with Bcl-2 expression and the caspase cascade in spermatogenesis, [37],[38] while the ERK signal pathway plays an important role in the activation of cellular processes involved in spermatogenesis including testicular heat shock and testicular torsion. [39],[40] Here, we have further confirmed that JNK, p38-MAPK, and ERK could be activated by CaSR activation in testicular tissues from diabetic rats, in accordance with previous studies. [28],[41] Specific activation of CaSR by GdCl 3 further enhanced, while specific inhibition of GdCl 3 by NPS-2390 reduced the phosphorylation of the above three molecules. The results indicate that CaSR acts as an enhancer in the activation of the MAPK pathway.

In summary, the present study for the first time has demonstrated that CaSR, a well-known calcium-homeostasis regulator, participates in testicular damage in STZ-induced diabetes in rats. Diabetic rats had significantly lower testes weights and serum levels of testosterone compared to healthy controls. The testicular tissues of diabetic rats expressed higher levels of CaSR and had higher MDA content while having lower activities of SOD and GSH-Px and higher numbers of apoptotic germ cells. The diabetic testicular tissues also expressed lower levels of Bcl-2 and higher levels of Bax and cleaved caspase-3, which were associated with higher phosphorylation rates of JNK, p38, and ERK1/2. The above parameters could be further increased or aggravated by the administration of GdCl 3 , a specific activator of CaSR, and attenuated by NPS-2390, a specific inhibitor of CaSR. There are indeed several drawbacks of the present study, and further investigations should be conducted in the future. For instance, we did not measure levels of LH (luteinizing hormone) and FSH (follicle-stimulating hormone), which have been demonstrated to have an impact on spermatogonial development and are involved in testicular function in insulin-dependent diabetes. [42] More agonists or antagonists of CaSR should be applied for further investigation of the role of CaSR in diabetes-induced testicular damage. However, the preliminary results at least imply that CaSR may be a potential target for designing preventive or therapeutic strategies for protecting the testes from diabetes caused damage, thus preventing infertility in diabetic men.


  Competing Interests Top


The authors declare that they have no competing interests.


  Acknowledgments Top


This work was funded by grants from Natural Scientific Foundation of Heilongjiang Province, China (C201310).

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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