Renal ischemia/reperfusion induces prominent progressive kidney disease in diabetic mice.

Acute kidney injury (AKI) is a public health concern associated with high rates of mortality, even in milder cases. One of the reasons for the difficulty in managing AKI in patients is due to its association with pre-existing comorbidities, such as diabetes. In fact, diabetes increases the susceptibility to develop more severe AKI after renal ischemia. However, the long-term effects of this association are not known. Thus, an experimental model was designed to evaluate the chronic effects of renal ischemia/reperfusion (IR) in streptozotocin (STZ)-treated mice. We focused on the glomerular and tubulointerstitial damage, as well as kidney function and metabolic profile. It was found that pre-existing diabetes may potentiate progressive kidney disease after AKI, mainly by exacerbating proinflammatory and sustaining fibrotic responses and altering renal glucose metabolism. To our knowledge, this is the first report that highlights the long-term effects of renal IR on diabetes. The findings of this study can support the management of AKI in clinical practice.NEW & NOTEWORTHY This study demonstrated that early diabetes potentiates progressive kidney disease after ischemia/reperfusion (IR)-induced acute kidney injury, mainly by exacerbating pro-inflammatory and sustaining fibrotic responses and altering renal glucose metabolism. Thus, these findings will contribute to the therapeutic support of patients with type 1 diabetes with eventual renal IR intervention in clinical practice.

Angiotensin II-induced podocyte apoptosis is mediated by endoplasmic reticulum stress/PKC-δ/p38 MAPK pathway activation and trough increased Na+/H+ exchanger isoform 1 activity.

BACKGROUND: Angiotensin II (Ang II) contributes to the progression of renal diseases associated with proteinuria and glomerulosclerosis mainly by inducing podocyte apoptosis. In the present study, we investigated whether the chronic effects of Ang II via AT1 receptor (AT1R) would result in endoplasmic reticulum (ER) stress/PKC-delta/p38 MAPK stimulation, and consequently podocyte apoptosis. METHODS: Wistar rats were treated with Ang II (200 ng·kg-1·min-1, 42 days) and or losartan (10 mg·kg-1·day-1, 14 days). Immortalized mouse podocyte were treated with 1 µM Ang II and/or losartan (1 µM) or SB203580 (0.1 µM) (AT1 receptor antagonist and p38 MAPK inhibitor) for 24 h. Kidney sections and cultured podocytes were used to evaluate protein expression by immunofluorescence and immunoblotting. Apoptosis was evaluated by flow cytometry and intracellular pH (pHi) was analyzed using microscopy combined with the fluorescent probe BCECF/AM. RESULTS: Compared with controls, Ang II via AT1R increased chaperone GRP 78/Bip protein expression in rat glomeruli (p < 0.001) as well as in podocyte culture (p < 0.01); increased phosphorylated eIf2-α (p < 0.05), PKC-delta (p < 0.01) and p38 MAPK (p < 0.001) protein expression. Furthermore, Ang II induced p38 MAPK-mediated late apoptosis and increased the Bax/Bcl-2 ratio (p < 0.001). Simultaneously, Ang II via AT1R induced p38 MAPK-NHE1-mediated increase of pHi recovery rate after acid loading. CONCLUSION: Together, our results indicate that Ang II-induced podocyte apoptosis is associated with AT1R/ER stress/PKC-delta/p38 MAPK axis and enhanced NHE1-mediated pHi recovery rate.

The Role of ß-Adrenergic Overstimulation in the Early Stages of Renal Injury.

BACKGROUND/AIMS: To assess the possible contribution of the ß-adrenergic overstimulation in early stages of renal injury, the present study evaluated, in rats, the effects of the ß-adrenoceptor agonist isoproterenol (ISO) on renal function and morphology, as well as the renal mRNA and protein expression of the NADPH oxidase isoform 4 (Nox 4) and subunit p22phox, endoplasmic reticulum (ER) stress, pro-inflammatory, pro-apoptotic and renin-angiotensin system (RAS) components. METHODS: Wistar rats received ISO (0.3 mg.kg-1.day-1 s.c.) or vehicle (control) for eight days. At the end of the treatment, food and water intake, urine output and body weight gain were evaluated and renal function studies were performed. Renal tissue was used for the morphological, quantitative PCR and immunohistochemical studies. RESULTS: ISO did not change metabolic parameters or urine output. However it induced a decrease in renal blood flow and an increase in the filtration fraction. These changes were accompanied by increased cortical mRNA and protein expression for the renal oxidative stress components including Nox 4 and p22phox; ER stress, pro-inflamatory, pro-apoptotic as well as RAS components. ISO also induced a significant increase in medullar renin protein expression. CONCLUSION: These findings support relevant information regarding the contribution of specific ß-adrenergic hyperactivity in early stage of renal injury, indicating the reactive oxygen species, ER stress and intrarenal RAS as important factors in this process.

Early type 1 diabetes aggravates renal ischemia/reperfusion-induced acute kidney injury.

The present study aimed to investigate the interaction between early diabetes and renal IR-induced AKI and to clarify the mechanisms involved. C57BL/6J mice were assigned to the following groups: (1) sham-operated; (2) renal IR; (3) streptozotocin (STZ-55 mg/kg/day) and sham operation; and (4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 min followed by reperfusion for 48 h, at which time the animals were euthanized. Renal function was assessed by plasma creatinine and urea levels, as well urinary protein contents. Kidney morphology and gene and protein expression were also evaluated. Compared to the sham group, renal IR increased plasma creatinine, urea and albuminuria levels and decreased Nphs1 mRNA expression and nephrin and WT1 protein staining. Tubular injury was observed with increased Havcr1 and Mki67 mRNA expression accompanied by reduced megalin staining. Renal IR also resulted in increased SQSTM1 protein expression and increased proinflammatory and profibrotic factors mRNA expression. Although STZ treatment resulted in hyperglycemia, it did not induce significant changes in renal function. On the other hand, STZ treatment aggravated renal IR-induced AKI by exacerbating renal dysfunction, glomerular and tubular injury, inflammation, and profibrotic responses. Thus, early diabetes constitutes a relevant risk factor for renal IR-induced AKI.