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Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high‐density lipoprotein (rHDL) ameliorated renal injury in eNOS−/−dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non‐diabetes), eNOS−/−dbdb (diabetes), and eNOS−/−dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS−/−dbdb mice at Week 16 at 5 μg/g body weight in ~100 μL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS−/−dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD. [ABSTRACT FROM AUTHOR]

Hyperglycemia and increased activity of the renal angiotensin II (ANG II) system are two primary pathogenic stimuli for the onset and progression of podocyte injury in diabetic nephropathy. However, the underlying mechanisms are not fully understood. Store-operated Ca2+ entry (SOCE) is an important mechanism that helps maintain cell Ca2+ homeostasis in both excitable and nonexcitable cells. Our previous study demonstrated that high glucose (HG) enhanced podocyte SOCE (1). It is also known that ANG II activates SOCE by releasing endoplasmic reticulum Ca2+. However, the role of SOCE in stress-induced podocyte apoptosis and mitochondrial dysfunction remains unclear. The present study was aimed to determine whether enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial damage. In kidneys of mice with diabetic nephropathy, the number of podocytes was significantly reduced. In cultured human podocytes, both HG and ANG II treatment induced podocyte apoptosis, which was significantly blunted by an SOCE inhibitor, BTP2. Seahorse analysis showed that podocyte oxidative phosphorylation in response to HG and ANG II was impaired. This impairment was significantly alleviated by BTP2. The SOCE inhibitor, but not a transient receptor potential cation channel subfamily C member 6 inhibitor, significantly blunted the damage of podocyte mitochondrial respiration induced by ANG II treatment. Furthermore, BTP2 reversed impaired mitochondrial membrane potential and ATP production and enhanced mitochondrial superoxide generation induced by HG treatment. Finally, BTP2 prevented the overwhelming Ca2+ uptake in HG-treated podocytes. Taken together, our results suggest that enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial injury. [ABSTRACT FROM AUTHOR]

Hyperglycemia and increased activity of the renal angiotensin II (ANG II) system are two primary pathogenic stimuli for the onset and progression of podocyte injury in diabetic nephropathy. However, the underlying mechanisms are not fully understood. Store-operated Ca 2+ entry (SOCE) is an important mechanism that helps maintain cell Ca 2+ homeostasis in both excitable and nonexcitable cells. Our previous study demonstrated that high glucose (HG) enhanced podocyte SOCE (1). It is also known that ANG II activates SOCE by releasing endoplasmic reticulum Ca 2+ . However, the role of SOCE in stress-induced podocyte apoptosis and mitochondrial dysfunction remains unclear. The present study was aimed to determine whether enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial damage. In kidneys of mice with diabetic nephropathy, the number of podocytes was significantly reduced. In cultured human podocytes, both HG and ANG II treatment induced podocyte apoptosis, which was significantly blunted by an SOCE inhibitor, BTP2. Seahorse analysis showed that podocyte oxidative phosphorylation in response to HG and ANG II was impaired. This impairment was significantly alleviated by BTP2. The SOCE inhibitor, but not a transient receptor potential cation channel subfamily C member 6 inhibitor, significantly blunted the damage of podocyte mitochondrial respiration induced by ANG II treatment. Furthermore, BTP2 reversed impaired mitochondrial membrane potential and ATP production and enhanced mitochondrial superoxide generation induced by HG treatment. Finally, BTP2 prevented the overwhelming Ca 2+ uptake in HG-treated podocytes. Taken together, our results suggest that enhanced SOCE mediated HG- and ANG II-induced podocyte apoptosis and mitochondrial injury. NEW & NOTEWORTHY This study tested the hypothesis that overwhelming store-operated Ca 2+ entry is a novel mechanism contributing to high glucose- and angiotensin II-induced podocyte apoptosis and mitochondrial injury.

Obese Zucker rats (OZRs) develop hypertension and hyperinsulinemia by 3 mo of age. Male OZRs also have diminished baroreflex-mediated activation of nucleus tractus solitarius (NTS) and bradycardia, which are improved by correcting their hyperglycemia. Conversely, 3-mo-old female OZRs and lean Zucker rats (LZRs) have equivalent baroreflex-mediated bradycardia that is impaired in 6-mo-old OZRs. We hypothesized that 3-mo-old female OZRs maintain NTS activation and baroreflexes coincident with glycemic control. We also hypothesized that 6-mo-old female OZRs develop impaired baroreflexes with hyperglycemia and diminished NTS activation. In 12- to 16-wk-old females, sympathetic nerve activity (SNA) and arterial pressure (AP) were higher in OZRs than LZRs. However, baroreflex-mediated inhibition of SNA and bradycardia were equivalent in female OZRs and LZRs. Unlike deficits in male OZRs, female OZRs and LZRs had no differences in phenylephrine-induced c-Fos expression in NTS or decreases in SNA and AP evoked by glutamate into NTS. Compared with hyperglycemia in male OZRs (217.9 ± 34.4 mg/dL), female OZRs had normal fed blood glucose levels (108.2 ± 1.6 mg/dL in LZRs and 113.6 ± 3.5 mg/dL in OZRs) with emerging glucose intolerance. Conscious 24- to 27-wk-old female OZRs had impaired baroreflex-mediated bradycardia, but fed blood glucose was modestly elevated (124.2 ± 5.2 mg/dL) and phenylephrine-induced c-Fos expression in NTS was comparable to LZRs. These data suggest that better glycemic control in 3-mo-old female OZRs prevents diminished NTS activation and baroreflexes, supporting the notion that hyperglycemia impairs these responses in male OZRs. However, 6-mo-old female OZRs had impaired baroreflex efficacy without diminished NTS activation or pronounced hyperglycemia, suggesting baroreflex deficits develop by different mechanisms in female and male OZRs.