Olfactory-like chemosensory signaling occurs outside of the olfactory epithelium. We find that major components of olfaction, including olfactory receptors (ORs), olfactory-related adenylate cyclase (AC3) and the olfactory G protein (Golf), are expressed in the kidney. AC3 and Golf colocalize in renal tubules and in macula densa (MD) cells which modulate glomerular filtration rate (GFR). GFR is significantly reduced in AC3 ؊/؊ mice, suggesting that AC3 participates in GFR regulation. Although tubuloglomerular feedback is normal in these animals, they exhibit significantly reduced plasma renin levels despite up-regulation of COX-2 expression and nNOS activity in the MD. Furthermore, at least one member of the renal repertoire of ORs is expressed in a MD cell line. Thus, key components of olfaction are expressed in the renal distal nephron and may play a sensory role in the MD to modulate both renin secretion and GFR.adenylate cyclase 3 ͉ glomerular filtration rate ͉ Golf ͉ macula densa ͉ renin

Serum creatinine is used clinically to detect and evaluate acute kidney injury (AKI) and chronic kidney disease (CKD), 1,2 although the limitations of serum creatinine for the early detection and accurate estimation of renal injury are widely known. In AKI, serum creatinine does not accurately reflect the GFR because the patient is not in steady state. 3 Furthermore, serum creatinine is also influenced by tubular creatinine secretion and by nonrenal factors such as muscle mass, liver function, and nonrenal (gastrointestinal) elimination.Sepsis remains a serious problem in critically ill patients, and mortality from sepsis is increased dramatically when complicated by AKI; therefore, early detection and accurate evaluation of AKI is important in patients with sepsis. We modified the cecal ligation and puncture (CLP) mouse sepsis model to make it more clinically relevant, and our model developed sepsis-induced AKI. 4 -6 We found that serum creatinine increased to a lesser extent in CLP (approximately 0.5 mg/dl) than ischemia/reperfusion or cisplatin administration (Ͼ1 mg/dl) within 24 h of injury. To explore nonrenal factors that might account for this disparity, we used bilateral nephrectomy (BNx), a technique used recently by others to study the contribution of the kidney to cytokine metabolism and acute lung injury. 7 First, we evaluated sepsis in bilaterally nephrectomized mice. We induced sepsis by CLP surgery with 8-mm cecal ligation, which causes modest sublethal sepsis in normal outbred CD-1 mice. 8 All animals survived until they were killed at 18 h after surgery. CLP surgery in non-nephrectomized mice caused a numerically small, but not significant increase of serum creatinine (sham BNx ϩCLP group). As expected, we found large increases of serum creatinine in the BNxϩsham CLP group; however, induction of sepsis at the time of BNx significantly decreased serum creatinine (BNxϩCLP group) compared with nonseptic BNx alone (BNxϩsham CLP group; Figure 1A), raising doubt about whether serum creatinine accurately reflects impaired kidney function during sepsis. In contrast, nonrenal organ injury markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]) and serum TNF-␣ were higher in the BNxϩCLP group than in the BNxϩsham CLP group, confirming the presence of severe sepsis (Figure 1, ABSTRACTAlthough diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-␣. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decrease...

The remnant kidney model in C57BL6 mice does not develop progressive chronic kidney disease (CKD). In this study we modified the model to mimic features of human CKD and to define accelerants of disease progression using three strains of mice. Following the procedure there was a progressive increase in albuminuria, progressive loss in renal function, severe glomerulosclerosis and interstitial fibrosis, hypertension, cardiac fibrosis, and anemia by 4 weeks in CD-1 mice and by 12 weeks in 129S3 mice. In contrast, even after 16 weeks, the C57BL/6 mice with a remnant kidney had modestly increased albuminuria without increased blood pressure and without developing CKD or cardiac fibrosis. The baseline blood pressure, determined by radiotelemetry in conscious animals, correlated with CKD progression rates in each strain. Administering angiotensin II overcame the resistance of C57BL/6 mice to CKD following renal mass reduction displaying high blood pressure and albuminuria, severe glomerulosclerosis, and loss of renal function by 4 weeks. Decreasing blood pressure with olmesartan but not hydralazine in CD-1 mice with a remnant kidney reduced CKD progression and cardiac fibrosis. C57BL/6 mice with a remnant kidney and DOCA-salt hypertension developed modest CKD. Each strain had similar degrees of interstitial fibrosis in three different normotensive models of renal fibrosis. Thus reducing renal mass in CD-1 or 129S3 mice mimics many features of human CKD. Angiotensin II can convert the C57BL/6 strain from CKD-resistant to susceptible in this disease model.