Postischemic inflammatory syndrome: a critical mechanism of progression in diabetic nephropathy

Abstract

Diabetes is a major epidemic, and diabetic nephropathy is the most common cause of end-stage renal disease. Two critical components of diabetic nephropathy are persistent inflammation and chronic renal ischemia from widespread vasculopathy. Moreover, acute ischemic renal injury is common in diabetes, potentially causing chronic kidney disease or end-stage renal disease. Accordingly, we tested the hypothesis that acute renal ischemia accelerates nephropathy in diabetes by activating proinflammatory pathways. Lean and obese-diabetic ZS rats (F(1) hybrids of spontaneously hypertensive heart failure and Zucker fatty diabetic rats) were subjected to bilateral renal ischemia or sham surgery before the onset of proteinuria. The postischemic state in rats with obesity-diabetes was characterized by progressive chronic renal failure, increased proteinuria, and renal expression of proinflammatory mediators. Leukocyte number in obese-diabetic rat kidney was markedly increased for months after ischemia. Intrarenal blood flow velocity was decreased after ischemia in lean control and obese-diabetic rats, although it recovered in lean rats. At 2 mo after ischemia, blood flow velocity decreased further in sham-surgery and postischemia obese-diabetic rats, so that RBC flow velocity was only 39% of control in the obese-diabetic rats after ischemia. In addition, microvascular density remained depressed at 2 mo in kidneys of obese-diabetic rats after ischemia. Abnormal microvascular permeability and increases in interstitial fibrosis and apoptotic renal cell death were also more pronounced after ischemia in obese-diabetic rats. These data support the hypothesis that acute renal ischemia in obesity-diabetes severely aggravates chronic inflammation and vasculopathy, creating a self-perpetuating postischemia inflammatory syndrome, which accelerates renal failure.

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

“…The cells were rinsed with PBS and imaged with a Zeiss LSM 510 confocal microscope equipped with UV, argon, and helium lasers (15). Apoptotic cells in culture and in kidney sections were identified as those with condensed, fragmented nuclei and expressed as the fraction of total nuclei in the image (14).…”

“…The rats were anesthetized with intraperitoneal (ip) pentobarbital sodium (50 mg/kg) and placed on a homeothermic table to maintain core body temperature at ϳ37°C. After adequate anesthesia was ensured, renal ischemia was induced by occluding both renal pedicles for 30 min with microaneurysm clamps as described (14). In two other separate groups of rats, acute renal failure was caused with either gentamicin (100 mg·kg Ϫ1 ·day Ϫ1 twice daily for 7 days) or cisplatin (7.5 mg/kg ip, once).…”

“…Accordingly, factors that participate in kidney development have also being tested on AKI, including bone morphogenetic protein (28), glial cell line-derived neutrophic growth factor (25), and notch pathway ligand DLL4 (8). Current work has demonstrated a strong renal inflammatory component following AKI (14), and some have reported that mediators of inflammation could also be beneficial in AKI (4). The notion that components of inflammation can be protective is supported by our work showing that serum amyloid A protein (SAA), a classic component of the acutephase reaction linked to inflammation, also promotes tubulogenesis (15).…”

Mechanisms of Tubulointerstitial Fibrosis

“…107 In early stages of injury the peritubular vasculature is damaged by proapoptotic stimuli, particularly transient ischemia. 255,256 Progressive fibrosis then remodels the peritubular endothelial network governed by imbalance among pro-and antiangiogenic stimuli 257,258 or loss of peritubular endothelial cells by EndMT-forming fibroblasts. 50, 259 The fibrotic tubulointerstitium is a hypoxic environment.…”

Neutrophil-to-Lymphocyte Ratio as a Predictor of Worsening Renal Function in Diabetic Patients (3-Year Follow-Up Study)

“…[10][11][12][13][14][15][16] Inflammation secondary to ischemia and endothelial dysfunction was found to be associated with the development of DN. [17][18][19] Some medications were found to slow down the progression of DN through suggested antiinflammatory actions. [20][21][22][23][24][25][26] Neutrophil to lymphocyte ratio (NLR) rather than other white cell parameters (e.g., total white cell, monocyte count, and absolute neutrophil count) was found to be a useful inflammatory marker that predicts adverse outcomes in many medical and surgical conditions.…”