Regression of glomerulosclerosis in response to transient treatment with angiotensin II blockers is attenuated by blockade of matrix metalloproteinase-2

Understanding mechanisms that contribute to the regression of glomerulosclerosis is important for developing new strategies to treat chronic kidney disease. We reported that transient high-dose treatment with an angiotensin receptor blocker causes regression of renal arteriolar hypertrophy and hypertension in spontaneously hypertensive rats. To extend those findings to another form of kidney disease, we examined the short- and long-term effects of transient high-dose angiotensin receptor blocker treatment in a mouse model of adriamycin-induced glomerulosclerosis. A 2-week course of candesartan caused a dose-dependent regression of established glomerulosclerotic lesions sustained for over 6 months following cessation of treatment. Highly sensitive in situ zymography and activity assays showed that glomerular matrix metalloproteinase (MMP)-2 activity was increased after high-dose angiotensin blocker therapy. Treatment of cultured podocytes with candesartan resulted in an increase in MMP-2 activity. The regression of glomerulosclerosis was partially attenuated in mice pretreated with the MMP inhibitor doxycycline, as well as in MMP-2 knockout mice. Our results suggest that transient high-dose angiotensin receptor blocker treatment effectively induced sustained regression of glomerulosclerosis by a mechanism mediated, in part, by changes in MMP-2 activity

Elucidation of the mechanism of subunit exchange in αB crystallin oligomers

AlphaB crystallin (αB-crystallin) is a key protein for maintaining the long-term transparency of the eye lens. In the eye lens, αB-crystallin is a “dynamical” oligomer regulated by subunit exchange between the oligomers. To elucidate the unsettled mechanism of subunit exchange in αB-crystallin oligomers, the study was carried out at two different protein concentrations, 28.5 mg/mL (dense sample) and 0.45 mg/mL (dilute sample), through inverse contrast matching small-angle neutron scattering. Interestingly, the exchange rate of the dense sample was the same as that of the dilute sample. From analytical ultracentrifuge measurements, the coexistence of small molecular weight components and oligomers was detected, regardless of the protein concentration. The model proposed that subunit exchange could proceed through the assistance of monomers and other small oligomers; the key mechanism is attaching/detaching monomers and other small oligomers to/from oligomers. Moreover, this model successfully reproduced the experimental results for both dense and dilute solutions. It is concluded that the monomer and other small oligomers attaching/detaching mainly regulates the subunit exchange in αB-crystallin oligomer

Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Sirtuin 1 (Sirt1), a NAD[superscript +]-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant 22790800

Cardiac hypertrophy in chronic kidney disease—role of Aldosterone and FGF23

Abstract Cardiac hypertrophy is a life-threatening disorder and is frequently observed in patients with chronic kidney disease (CKD). Much attention has been focused on the derangement in hormonal factors, including aldosterone and FGF23, as novel causes of cardiac hypertrophy in CKD. Plasma aldosterone concentrations are elevated as renal function declines. Although aldosterone antagonists are available for the treatment of hypertension with cardiac hypertrophy, concern remains regarding the possible occurrence of serious hyperkalemia. Alternatively, certain types of calcium channel blockers suppress aldosterone synthesis or exert blocking action for mineralocorticoid receptors and could halt the progression of cardiac dysfunction. Recently, FGF23 is shown to be elevated as CKD progresses and may be responsible for the development of cardiac hypertrophy and heart failure. Furthermore, FGF23 not only inhibits the renal expression of angiotensin converting enzyme 2 but also enhances renin gene transcription, both of which could accelerate renin-angiotensin-aldosterone system. Although the increase in serum phosphate concentrations is a pivotal stimulus for FGF23 production, recent studies suggest that reduced iron status and elevated aldosterone levels, frequently seen in patients with CKD or on dialysis, might also contribute to the elevation in serum FGF23 levels. Conversely, phosphate binders and appropriate iron status could reduce serum FGF23, potentially leading to the alleviation of cardiac hypertrophy and heart failure. In conclusion, novel therapeutic strategies associated with aldosterone and FGF23 may confer a benefit in the management of cardiac disorders in CKD

Therapeutic effect of nintedanib on acute exacerbation of interstitial lung diseases

Although the development of new antifibrotic agents (pirfenidone, nintedanib) has modified the disease progression of idiopathic pulmonary fibrosis (IPF), there is still no effective treatment for acute exacerbation of interstitial lung diseases (ILD) including IPF. We herein report a case of acute exacerbation of ILD (AE-ILD) treated only with nintedanib without any environmental changes and any other medications such as corticosteroid therapy, diuretic and anti-biotics, which resulted in the gradual improvement of the patient's clinical symptoms, high-resolution computed tomography findings, and forced vital capacity. This case might suggest the possibility that nintedanib not only modifies the disease progression of Idiopathic Pulmonary Fibrosis (IPF), but also facilitate the recovery from the acute exacerbation of ILD

Tetraaza[1₄]- and Octaaza[1₈]paracyclophane: Synthesis and Characterization of Their Neutral and Cationic States

Two kinds of aza­[1_<i>n</i>]­paracyclophanes, tetraaza­[1₄]­paracyclophane (<b>P4</b>) and octaaza­[1₈]­paracyclophane (<b>P8</b>), were synthesized as the smallest and the largest monodisperse macrocyclic oligomers of polyaniline ever made. Herein we report the electronic nature of the cationic species of these two macrocycles with different ring size. By combining ESR spectroscopy and DFT calculations it was suggested that <b>P4</b>^·+ was classified as delocalized class III or poised on the class II/III borderline while <b>P8</b>^·+ was regarded as a localized class II mixed-valence system. We successfully isolated the dication of <b>P4</b> as a stable dicationic salt <b>P4</b>²⁺·2­[SbF₆]⁻, and the structure of <b>P4</b>²⁺ was determined by X-ray crystal analysis. Variable-temperature NMR measurements for <b>P4</b>²⁺·2­[SbF₆]⁻ unequivocally showed that <b>P4</b>²⁺ was a 22π electron system with a singlet ground state. The supercharged hexacation of <b>P8</b> was also isolated as <b>P8</b>⁶⁺·6­[SbCl₆]⁻, and X-ray crystal analysis revealed that <b>P8</b>⁶⁺ includes one SbCl₆^– anion in its macrocyclic cavity