Tubulointerstitium as Predictor of Progression of Glomerular Diseases

alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO 3 feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O 2 ⅐ Ϫ -induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.

Section: Fluorescence Activated Cell Sorting (Facs) Analysis Of Intramentioning

confidence: 99%

“…[1][2][3] Reactive oxygen species (ROS) are among the most toxic cellular factors that directly induce tubulointerstitial injury. 4 -6 ROS are abundantly generated in the proximal tubular cells through the reabsorption of urinary albumin.…”

mentioning

confidence: 99%

Luminal Alkalinization Attenuates Proteinuria-Induced Oxidative Damage in Proximal Tubular Cells

Souma¹,

Abe²,

Moriguchi³

et al. 2011

“…Expansion of the interstitial compartment is a major component of IF/ TA. Multiple studies have demonstrated a direct relationship between interstitial expansion and renal allograft functional decline [3][4][5] and graft failure. [6][7][8][9][10] Interstitial expansion is amenable to angiotensinconverting enzyme (ACE) inhibition.…”

mentioning

confidence: 99%

Angiotensin II Blockade in Kidney Transplant Recipients

Ibrahim

Jackson

Connaire

et al. 2013

Interstitial fibrosis/tubular atrophy (IF/TA) contributes to the loss of kidney allografts, and treatment or preventive options are lacking. We conducted a double-blind, randomized, placebo-controlled trial to determine whether angiotensin II blockade prevents the expansion of the cortical interstitial compartment, the precursor of fibrosis. We randomly assigned 153 transplant recipients to receive losartan, 100 mg (n=77), or matching placebo (n=76) within 3 months of transplantation, continuing treatment for 5 years. The primary outcome was a composite of doubling of the fraction of renal cortical volume occupied by interstitium from baseline to 5 years or ESRD from IF/TA. In the intention-to-treat analysis, using only patients with adequate structural data, the primary endpoint occurred in 6 of 47 patients who received losartan and 12 of 44 who received placebo (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.13-1.15; P=0.08). We found no significant effect of losartan on time to a composite of ESRD, death, or doubling of creatinine level. In a secondary analysis, losartan seemed to reduce the risk of a composite of doubling of interstitial volume or all-cause ESRD (OR, 0.36; 95% CI, 0.13-0.99; P=0.05), but this finding requires validation. In conclusion, treatment with losartan did not lead to a statistically significant reduction in a composite of interstitial expansion or ESRD from IF/TA in kidney transplant recipients.

“…1 Chronic proteinuria and tubulointerstitial fibrosis, characteristics of established DN, correlate best with the degree of renal dysfunction and are considered reliable prognostic indicators for ESRD. [2][3][4][5][6] In fact, proteinuria per se has been postulated to contribute to progressive tubulointerstitial fibrosis in general. 7 In this context, it has been proposed that urinary protein represents a direct stress for renal tubular epithelial cells.…”

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confidence: 99%

Proteinuria and Hyperglycemia Induce Endoplasmic Reticulum Stress

Lindenmeyer

Rastaldi²,

Ikehata³

et al. 2008

238

214

The endoplasmic reticulum (ER) is an important site for protein folding and becomes "stressed" when its capacity to fold proteins is overwhelmed. In response, "unfolded protein response" (UPR) genes are induced, increasing the capacity to fold proteins; if the response is insufficient, then apoptosis ensues. For investigation of whether proteinuria and hyperglycemia induce ER stress in renal epithelial cells, microarray data from biopsies of established diabetic nephropathy (DN) were analyzed. Expression of UPR genes was significantly different in these biopsies than in control kidneys or biopsies of patients with mild DN, suggesting an association between the degree of DN and UPR gene expression. Expression of the transcription factor XBP1 and the ER chaperones HSPA5 and HYOU1 were increased, but the proapoptotic gene DDIT3 was unchanged. These findings were replicated in an independent cohort of patients with established DN by real-time reverse transcriptase-PCR. Immunofluorescence of renal biopsies from patients with DN confirmed the upregulation for HSPA5 and HYOU1 proteins in tubular epithelia. In biopsies of minimal-change disease, the mRNA levels of some ER stress molecules were also induced, but protein expression of HSPA5 and HYOU1 remained significantly lower than that observed in DN. Exposure of renal tubular epithelial cells to albumin and high glucose in vitro enhanced expression of genes involved in ER stress. These observations suggest that in proteinuric diseases, tubular epithelial cells undergo ER stress, which induces an adaptive, protective UPR. Although this may protect the cells from ER stress, persistence of hyperglycemia and proteinuria may eventually lead to apoptosis.