Increased thromboxane/prostaglandin receptors contribute to high glucose-induced podocyte injury and mitochondrial fission through ROCK1-Drp1 signaling.

Excessive mitochondrial fission in podocytes serves as a central hub for the pathogenesis of diabetic nephropathy (DN), and the thromboxane/prostaglandin receptor (TP receptor) plays a potential role in DN. However, regulation of the TP receptor during mitochondrial dynamics disorder in podocytes remains unknown. Here, we firstly reported novel mechanistic details of TP receptor effects on mitochondrial dynamics in podocytes under diabetic conditions. Expression of the TP receptor was significantly upregulated in podocytes under diabetic conditions both in vivo and in vitro. S18886 attenuated podocyte mitochondrial fission, glomerular injury and renal dysfunction in diabetic mice. Furthermore, inhibition of the TP receptor by both genetic and pharmacological methods dramatically reduced mitochondrial fission and attenuated podocyte injury induced by high glucose through regulating dynamin-related protein 1 (Drp1) phosphorylation and its subsequent translocation to mitochondria. In contrast, TP receptor overexpression and application of TP receptor agonist U46619 in these podocytes showed the opposite effect on mitochondrial fission and podocyte injury. Furthermore, treatment with Y27632, an inhibitor of Rho-associated kinase1 (ROCK1), significantly blunted more fragmented mitochondria and reduced podocyte injuries in podocytes with TP receptor overexpression or after U46619 treatment. Finally, pharmacological inhibition of Drp1 alleviated excessive mitochondrial fragmentation and podocyte damage in TP receptor overexpressing podocytes. Our data suggests that increased expression of the TP receptor can occur in a human cultured podocyte cell line and in podocytes derived from streptozotocin (STZ)-induced diabetic mice, which contributes to mitochondrial excessive fission and podocyte injury via ROCK1-Drp1 signaling.

Ambulatory blood pressure is better associated with target organ damage than clinic blood pressure in patients with primary glomerular disease.

BACKGROUND: Blood pressure is an important and modifiable cardiovascular risk factor. Ambulatory blood pressure monitoring (ABPM) provides valuable prognostic information in patients with chronic kidney disease (CKD), yet little is known about the association of various types of BP measurements with target organ damage (TOD) in patients with primary glomerular disease. The goal of this study was to investigate whether ambulatory blood pressure is better associated with TOD than clinic blood pressure in patients with primary glomerular disease. METHODS: 1178 patients with primary glomerular disease were recruited in this cross-sectional study. TOD were assessed by the following 4 parameters: left ventricular mass index (LVMI or LVH, left ventricular hypertrophy), estimated glomerular filtration rate (eGFR< 60 ml/min/1.73m2), albumin-to-creatinine ratio (ACR ≥ 30 mg/g) and carotid intima-media thickness (cIMT) or plaque. Receiver operating characteristic (ROC) curve and multivariate logistic regression analyses were used to evaluate the relationship between ambulatory or clinic systolic blood pressure (SBP) indexes and TOD. RESULTS: Among 1178 patients (mean age, 39 years,54% men), 116, 458, 1031 and 251 patients had LVH, eGFR < 60 ml/min/1.73m2, ACR ≥ 30 mg/g and cIMT≥0.9 mm or plaque respectively. Area under ROC curves for TOD in ambulatory SBP, especially nighttime SBP, was greater than that in clinic SBP (P < 0.05). Multivariate logistic regression analyses showed that 24 h SBP, daytime SBP and nighttime SBP were significantly associated with LVH, eGFR< 60 ml/min/1.73m2 and ACR ≥ 30 mg/g after adjustment for clinic SBP, while the association of clinic SBP was attenuated after further adjustment for nighttime SBP. CONCLUSIONS: Ambulatory blood pressure, especially nighttime blood pressure, is probably superior to clinic blood pressure and has a significant association with TOD in primary glomerular disease patients.

Increased long noncoding RNA maternally expressed gene 3 contributes to podocyte injury induced by high glucose through regulation of mitochondrial fission.

Excessive mitochondrial fission plays a key role in podocyte injury in diabetic kidney disease (DKD), and long noncoding RNAs (lncRNAs) are important in the development and progression of DKD. However, lncRNA regulation of mitochondrial fission in podocytes is poorly understood. Here, we studied lncRNA maternally expressed gene 3 (Meg3) in mitochondrial fission in vivo and in vitro using human podocytes and Meg3 podocyte-specific knockdown mice. Expression of lncRNA Meg3 in STZ-induced diabetic mice was higher, and correlated with the number of podocytes. Excessive mitochondrial fission of podocytes and renal histopathological and physiological parameters were improved in podocyte-specific Meg3 knockdown diabetic mice. Elongated mitochondria with attenuated podocyte damage, as well as mitochondrial translocation of dynamin-related protein 1 (Drp1), were decreased in Meg3 knockout podocytes. By contrast, increased fragmented mitochondria, podocyte injury, and Drp1 expression and phosphorylation were observed in lncRNA Meg3-overexpressing podocytes. Treatment with Mdivi1 significantly blunted more fragmented mitochondria and reduced podocyte injury in lncRNA Meg3-overexpressing podocytes. Finally, fragmented mitochondria and Drp1 mitochondrial translocation induced by high glucose were reduced following treatment with Mdivi1. Our data show that expression of Meg3 in podocytes in both human cells and diabetic mice was higher, which regulates mitochondrial fission and contributes to podocyte injury through increased Drp1 and its translocation to mitochondria.

Nocturnal pulse rate correlated with ambulatory blood pressure and target organ damage in patients with chronic kidney disease.

The relationship between resting pulse rate (PR) and the occurrence of hypertension and cardiovascular (CV) mortality has been described in the general population. Few studies have examined the relationship between ambulatory PR, ambulatory blood pressure (BP), and target organ damage (TOD) in patients with chronic kidney disease (CKD). A total of 1509 patients with CKD were recruited in our hospital. Ambulatory blood pressure monitoring (ABPM) over a 24-hours period was performed and referenced with clinical data in this cross-sectional study. TOD was measured by estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), and carotid intima-media thickness (cIMT). Univariate and multivariate analyses were used to evaluate the relationship between PR, BP, and TOD. The percentage of male patients was 58.3% with a mean age of 44.6 ± 16.2 years. Nocturnal PR rather than 24-hours PR or daytime PR was an independent risk factor for clinical hypertension, 24-hours hypertension, BP dipper state, poor renal function, and LVH. In addition, the authors found that nighttime PR >74 beats/min (bpm) group was independently associated with clinical hypertension, 24-hours hypertension, day and night hypertension, nondipping BP, lower eGFR, and LVH when compared with nighttime PR <64 bpm group. Furthermore, 1:1 propensity score matching between PR ≤74 bpm group and PR >74 bpm group was performed. Multivariate analyses indicated nighttime PR >74 bpm remained independently associated with clinical hypertension, daytime and nighttime hypertension, and LVH. An increased nocturnal PR is associated with TOD, higher BP, and nondipping BP in patients with CKD.