Masaki Ryuzaki

Involvement of activated prorenin in the pathogenesis of slowly progressive nephropathy in the non-clipped kidney of two kidney, one-clip hypertension

The handle region peptide (HRP), a (pro)renin receptor (P)RR blocker, did not prevent the acute nephropathy occurring 2 weeks after clipping in renovascular hypertensive rats. This study was performed to examine the effects of HRP, its scramble peptide, or a saline vehicle on slowly progressive nephropathy occurring in the kidneys of two-kidney, one-clip Goldblatt hypertensive rats. At 2 weeks after clipping, the renal morphology in the clipped and non-clipped kidneys was similar in the three groups of rats. At 12 weeks after clipping, however, the glomerulosclerosis index (GI) and the tubulointerstitial damage (TD) of the non-clipped kidneys of the HRP-treated rats were significantly lower than those of vehicle-treated rats, although the GI and the TD were similar in the rats treated with scramble peptide and vehicle. The GI and the TD of the clipped kidneys were similar in the three groups of rats at 12 weeks after clipping. In the non-clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and transforming growth factor (TGF)-β mRNA levels of HRP-treated rats were significantly lower than those of vehicle-treated rats, although they were similar in the non-clipped kidneys from the rats treated with scramble peptide and vehicle. In the clipped kidneys at 12 weeks after clipping, activated prorenin levels, angiotensin II levels and TGF-β mRNA levels were similar in the three groups of rats. These results suggest that the ((P)RR)-dependent activation of prorenin contributes to the pathogenesis of slowly progressive nephropathy in the intact kidney in a rat model of renovascular hypertension.

Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid

Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5-aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance.

Sudden Onset of Pyrexia and Severe Blood Pressure Elevation Due to IL-6Production by Pheochromocytoma

We report a case of pheochromocytoma presenting with a sudden change in clinical manifestation. The change in the serum Interleukin-6 (IL-6) and histological examination indicated that this clinical presentation was caused by IL-6 elevation secondary to pheochromocytoma. This rare tumor should be considered in the differential diagnosis of fever of unknown origin, and prompt and appropriate administration of an alpha-1 blocker is highly recommended, especially for patients with large pheochromocytomas.

TRANSIENT SALT LOADING CAUSES PERSISTENT HYPERTENSION THROUGH EPIGENETIC MODIFICATION OF THE RENAL ARTERIOLES

Objective: We have previously reported that the medial hypertrophy of the renal arterioles induced by transient salt loading causes sustained elevation of blood pressure in spontaneous hypertensive rat (SHR) even after the salt loading had completed [Oguchi et al. Hypertension 2014]. Epigenetic modification of gene expression has attracted attention as a possible mechanism for sustained biological effects and onset of hypertension. The present study investigated the significance of histone acetylation in each segment of the kidney in the induction of hypertension after transient salt loading. Design and method: C57bl6 mice were implanted deoxycorticosterone acetate (DOCA) pellets and given drinking water containing 1% NaCl for 2 weeks to induce hypertension. We evaluated blood pressure, histological findings and gene expressions of the kidney during and after the transient salt loading. The degree of histone acetylation was assessed by immunostaining of acetylated H3 and H4 in each segment of the kidney including renal arterioles, segmental arteries, glomeruli and tubules. Gene expressions were examined in each segment of the kidney collected by laser capture microdissection (LCM). Results: Transient salt loading caused elevation in blood pressure during and even after stopping salt loading associated with persistent medial hypertrophy of renal arterioles. In the media of renal arterioles, histone acetylation was enhanced during salt loading, and the enhanced histone acetylation persisted even after stopping salt loading. The gene expression of MMPs in the renal arterioles collected by LCM increased during salt loading, and did not decline even after stopping salt loading. On the other hand, in the segmental arteries, neither hyper-acetylation nor hyper-expression of MMPs was observed. Also, in the tubules, enhanced histone acetylation by the salt loading returned to the initial level after the completion. Conclusions: The persistent medial hypertrophy along with focally sustained histone hyper-acetylation and elevation in MMPs expressions in the renal arterioles were suggested to cause sustained elevation of blood pressure after transient salt loading. The focal epigenetic modification in the kidney due to environmental factors would participate in the onset of persistent hypertension.

A MASS IMAGING TECHNIQUE REVEALED A RENO-PROTECTIVE EFFECT OF THE XANTHINE OXIDASE INHIBITOR FEBUXOSTAT IN THE ISCHEMIC KIDNEY BY PROMOTING ATP RECOVERY IN THE CORTEX

Objective: The kidney has different energy metabolism depending on the region. However, the distribution of phosphorylated adenosine (ATP, ADP and AMP) and their alteration after transient ischemia have not been known due to the technical difficulties. Design and method: Imaging mass spectrometry (IMS) with metabolome analysis is a novel technique to quantify the small metabolites in the tissues. We performed the IMS analysis in the ischemic kidney after transient ischemia by renal artery clipping. Results: In the normal kidney, ATP was significantly rich in both the cortex and outer medulla. After transient ischemia, ATP in the cortex degraded and the energy charge value decreased within a minute. ATP in the inner medulla did not decrease within a minute and needed 10 minutes to start decreasing. After the 10 minutes of ischemia, total adenylates decreased in the cortex, although the decrease in energy charge value was homogeneous in the kidney. During the 24 hours reperfusion after 10 minutes ischemia, restoration of total adenylates in the cortex was not sufficient. Febuxostat is a xanthine oxidase inhibitor which might promote reuse of hypoxanthine as a progenitor of adenylates and therefore might improve the restoration of total adenylates and ATP after transient ischemia. The administration of febuxostat in accordance with the reperfusion period supported the restoration of ATP level in the cortex and improved renal function which was impaired by transient ischemia. Conclusions: In these ways, IMS revealed the region-specific alteration of phosphorylated adenosine the ischemic kidney and the novel effect of febuxostat on the restoration of total adenylates and ATP in the cortex after transient ischemia.

ACUTE KIDNEY INJURY WITH KARYOMEGALIC INTERSTITIAL NEPHRITIS AFTER NIVOLUMAB TREATMENT - TWO CASE REPORTS

Objective: Background: Acute kidney injury (AKI) caused by immune checkpoint inhibitors are poorly described. Herein, we present 2 cases of AKI in patients under nivolumab treatment. Each case displayed acute interstitial nephritis (AIN) with karyomegalic interstitial nephritis (KIN), which was successfully treated with the discontinuation of nivolumab or the administration of corticosteroid. Design and method: Case 1: A 76-year old male with pancreatic cancer was admitted for AKI (serum creatinine (SCr) level from 0.84 to 3.08 mg/dL) after a series of nivolumab treatment. Five months after the initiation of nivolumab, he suffered from edema in his lower extremities along with the elevation of blood pressure (BP) to 170/97 mmHg. Kidney biopsy showed AIN where tubular epithelial cells with variably sized nuclei that were massively enlarged, irregularly shaped, and abnormally hyperchromatic, which findings were indicative of KIN. Approximately one year after quitting nivolumab treatment, his renal function improved to SCr level of 1.42 mg/dL, Results: Case 2: A 76-year old female with non-small cell lung cancer started treatment by nivolumab. Two months later, she exhibited AKI (SCr level from 0.81 to 1.54 mg/dL). Kidney biopsy revealed tubular injury with interstitial infiltration of inflammatory cells. Of note, tubular epithelial cells were focally enlarged with hyperchromatic nuclei, which finding was consistent with that of KIN. Since most of the enlarged tubular epithelial cells were positive for Ki-67, karyomegalic changes of tubular epithelia are suggested to be associated with the cell cycle abnormalities of tubular cells. The patient was administrated high dose of corticosteroid, and SCr level returned to that of her baseline. Conclusions: Conclusion: This is the first report of characteristic histological findings of KIN in nivolumab-associated AIN. The association of nivolumab-induced AIN with cell cycle derangement in our patients suggests that the activation of effector T cell by nivolumab may affect the proliferation of tubular epithelial cells, thereby leading to karyomegalic changes. In addition to the discontinuation of nivolumab, the administration of corticosteroid successfully improved renal function.

The Relationships between the Differences in the Central Blood Pressure and Brachial Blood Pressure and Other Factors in Patients with Essential Hypertension

Objective The management of blood pressure (BP) in hypertensive patients is the key to preventing a progression of organ damage. The brachial BP (bBP) has been used as the representative method for measuring the BP. The central BP (cBP), which is, different from the bBP due to the propagation and the reflection of the pulse wave in the arterial system, has recently received attention because it can now be estimated non-invasively. We examined the relationships between the difference in the central systolic BP (csBP) and the brachial systolic BP (bsBP) (Δ) and other factors in hypertensive patients. Methods The bsBP and csBP were measured in patients with essential hypertension and the relationships between the bsBP, csBP, or Δ and background factors including age, the brain natriuretic peptide (BNP) level, the estimated glomerular filtration rate (eGFR), flow-mediated vasodilation (an index of vascular endothelial function), the cardio-ankle vascular index (CAVI, an index of arteriosclerosis), and the carotid intima-media thickness (an index of atherosis) were investigated. Results The data of 191 patients were analyzed. Although there was no significant correlation between the CAVI and the bsBP; positive correlations were observed between the CAVI and the csBP (r=0.249, p=0.001). The Δ value showed significant positive correlations with age, and the BNP, eGFR, and CAVI values. Conclusion The csBP is more strongly associated with arteriosclerosis than the bsBP. Moreover, the Δ value is more strongly associated with cardiac function, renal function, and arteriosclerosis than the bsBP or csBP. These data suggested that the Δ value may have a greater prognostic value than the bsBP or csBP and may be worth calculating in the clinical setting.